Boat tropanes

ABSTRACT

Radiopharmaceutical compounds are disclosed. A tropane compound is linked through the N atom at the 8-position to a chelating ligand capable of complexing technetium or rhenium to produce a neutral labeled complex that selectively binds to the dopamine transporter over the serotonin transporter with a ratio of 10 or more. These compounds can be prepared as separate diastereoisomers as well as a mixture of diastereoisomers. Also disclosed are radiopharmaceutical kits for preparing the labeled radiopharmaceutical compounds.

FIELD OF THE INVENTION

The present invention relates to coordination complexes comprising aradiolabeled ligand with high binding affinity and good selectivity forthe dopamine transporter (DAT). Such agents can be useful for the earlydiagnosis and treatment of neurodegenerative disorders.

BACKGROUND OF THE INVENTION

The dopamine transporter (DAT) plays a critical role in physiological,pharmacological and pathological processes in brain. The transportsystem is a primary mechanism for terminating the effects of synapticdopamine, thereby contributing to the maintenance of homeostasis indopamine systems. It also appears to be a principal target of cocaine inthe brain. (Kennedy and Hanbauer, J. Neurochem. 1983, 41, 172-178;Shoemaker et al., Naunyn-Schmeideberg's Arch. Pharmacol. 1985, 329,227-235; Reith et al., Biochem Pharmacol. 1986, 35, 1123-1129; Ritz etal., Science 1987, 237, 1219-1223; Madras et al., J. Pharmacol. Exp.Ther. 1989a, 251, 131-141; Bergman et al., J. Pharmacol. Exp. Ther.1989, 251, 150-155; Madras and Kaufman, Synapse 1994, 18, 261-275).Furthermore, the dopamine transporter may be a conduit for entry ofneurotoxins into dopamine containing cells.

The striatum has the highest levels of dopamine terminals in the brain.A high density of DAT is localized on dopamine neurons in the striatumand appears to be a marker for a number of physiological andpathological states. For example, in Parkinson's disease, dopamine isseverely reduced and the depletion of DAT in the striatum has been anindicator for Parkinson's disease (Schoemaker et al.,Naunyn-Schmeideberg's Arch. Pharmacol. 1985, 329, 227-235; Kaufman andMadras, Synapse 1991, 9, 43-49). Consequently, early or presymptomaticdiagnosis of Parkinson's disease can be achieved by the quantitativemeasurement of DAT depletion in the striatum. (Kaufman and Madras,Synapse 1991, 9, 43-49). Simple and noninvasive methods of monitoringthe DAT are quite important. Depletion could be measured by anoninvasive means such as brain imaging using a scintillation camerasystem and a suitable imaging agent (Frost et al., Ann. Neurology 1993,34, 423-431; Hantraye et al., Neuroreport 1992, 3, 265-268). Imaging ofthe dopamine transporter also would enable the monitoring of progressionof the disease and of reversal of the disease such as with therapiesconsisting of implants of dopamine neurons or drugs that retardprogression of the disease.

Other neuropsychiatric disorders, including Tourette's Syndrome andLesch Nyhan Syndrome and possibly Rett's syndrome, are also marked bychanges in DAT density. The DAT also is the target of the most widelyused drug for attention deficit disorder, methylphenidate. The capacityto monitor the transporter in persons suffering from this disorder canhave diagnostic and therapeutic implications. Furthermore, anage-related decline in dopamine neurons can be reflected by a decline inthe dopamine transporter (Kaufman and Madras, Brain Res. 1993, 611,322-328; van Dyck et al., J. Nucl. Med. 1995, 36, 1175-1181) and mayprovide a view on dopamine deficits that lie outside the realm ofneuropsychiatric diseases.

The density of the DAT in the brains of substance abusers has also beenshown to deviate from that in normal brain. For example, the density iselevated in post-mortem tissues of cocaine abusers (Little et al., BrainRes. 1993, 628, 17-25). On the other hand, the density of the DAT inchronic nonviolent alcohol abusers is decreased markedly. (Tiihonen etal., Nature Medicine 1995, 1, 654-657). Brain imaging of substanceabusers can be useful for understanding the pathological processes ofcocaine and alcohol abuse and monitoring restoration of normal brainfunction during treatment.

Accordingly, a radiopharmaceutical that binds to the DAT can provideimportant clinical information to assist in the diagnosis and treatmentof these various disease states.

In order to be effective as an imaging agent for the disorders describedabove, it must have a specific binding affinity and selectivity for thetransporter being targeted, e.g. DAT. Brain imaging agents must alsohave blood brain barrier (BBB) permeability. Yet, it has been difficultto produce a metal chelate which can cross the blood brain barrier whilestill retaining binding affinity and selectivity for its receptor site.Therefore, it is very desirable to find a suitable agent that satisfiesthese criteria and will complex with a desired radionuclide, such as^(99m)Tc.

In addition, to be an effective imaging agent, a specifictarget:nontarget ratio is necessary. In the case of an agent selectivefor DAT one must take into account the fact that the striatum, theregion of the brain having the highest density of the dopaminetransporter, also contains serotonin transporter (SET). The SET isnormally present at one-tenth to one-fifteenth the concentration of thedopamine transporter. Imaging agents that bind very strongly to DATsometimes also exhibit a degree of binding to SET. Although such anontarget binding typically poses no serious problem in the imaging ofnormal brains due to the greater number of DAT compared to SET, underdisease conditions in which DAT are selectively reduced (or in which SETmay be selectively increased), binding to the SET may make it difficultto quantify DAT. Moreover, binding to SET in other brain regions such asthe hypothalamus and thalamus can reduce striatal contrast and diminishaccuracy in localizing and imaging the striatum. Therefore, the targetto nontarget binding ratio of DAT:SET can be important. Presently, amongthe most effective compounds for viewing and quantifying the DAT arephenyltropane derivatives that are labelled with positron emitters, suchas ¹¹C and ¹⁸F, and gamma emitters, such as 123I.

The radionuclide, technetium-99m, ^(99m)Tc (T_(1/2)6.9 h, 140 KeV gammaray photon emission) is a preferred radionuclide for use in imagingbecause of its excellent physical decay properties and its chemistry.For example, its half-life of about 6 hours provides an excellentcompromise between rate of decay and convenient time frame for animaging study. Thus, it is much preferred to other radionuclides such as¹²³I, which has a substantially longer half life, or ¹⁸F, which has asubstantially shorter half-life, and which are much more difficult touse. Its emission characteristics also make it easy to image. Further,it can be conveniently generated at the site of use. ^(99m)Tc iscurrently the radionuclide of choice in diagnostic centers around theworld. It would be desirable to have a coordination complex withtechnetium for imaging DAT. Such a complex could be used for detectingconditions in which the DAT is useful as a marker.

However, a number of difficulties arise in the use of technetium forradioimaging agents because of its chemistry. For example, ^(99m)Tc musttypically be bound by a chelating agent. Consequently it is much moredifficult to design and prepare a ^(99m)Tc radioligand than it is toprepare a radioligand using other radionuclides such as ¹²³I, which canbe attached covalently to the ligand. The size of the chelating agentfor technetium also can create problems when using this radionuclide inimaging agents. This can be an especially difficult problem whenattempting to design receptor-based imaging agents using Tc.

Imaging agents being tested to determine their ability as diagnostictools for neurodegenerative diseases typically are ¹²³I labeledradioiodinated molecules. See, for example, RTI-55 (Boja, J. W., et al.,Eur. J. Pharmacol. 1991, 194, 133-134; Kaufman and Madras, Synapse,1992, 12, 99-111) or β-CIT (Neumeyer, J. L., et al., Med. Chem. 1991,34, 3144-3146) and an iodoallyltropane, altropane (Elmaleh, D. R., etal., U.S. Pat. No. 5,493,026.

Although the tropane family of compounds are known to bind to thedopamine transporter, the addition of bulky chelating ligands forbinding technetium or rhenium would be expected to affect potency andability to cross the blood brain barrier of the resulting labeledcomplex. Kung, et al., in Technetium and Rhenium in Chemistry andNuclear Medicine 4, eds. M. Nicolini, G. Bandoli, U. Mazzi, ServiziGrafici Editoriali, Padua, 1995, report that a ⁹⁹Tc-labelled N₂S₂ ligandcomplexed with an arylpiperazine known to have selective binding toserotonin_(1A) had only moderate binding affinity in vitro and failed topenetrate the intact blood-brain barrier.

It would be desirable to have a technetium or rhenium radio-labelled DATimaging agent which is capable of crossing the blood brain barrier andhas a high binding affinity and selectivity for the DAT.

SUMMARY OF THE INVENTION

The present invention provides radiopharmaceutical compounds that formcoordination complexes with a technetium or rhenium radionuclide andthat selectively bind to dopamine transporters, thereby providing novelradio labeled agents. Preferred such agents include radioimaging agentswhich are capable of crossing the blood brain barrier to image DAT inthe brain.

The compounds of the present invention comprise a tropane compoundlinked through the N atom at the 8-position to a chelating ligandcapable of complexing a technetium or rhenium radionuclide to produce aneutral labeled complex that selectively binds to the dopaminetransporter. These compounds can be prepared as separatediastereoisomers as well as a mixture of diastereoisomers.

Tropane compounds useful in the practice of the present invention bindto the dopamine transporter. Preferred radiopharmaceutical compounds ofthe invention can be represented by the following structural formula:

wherein

-   -   R₁ is α or β and is selected from COOR^(a), COR^(a), and        CON(CH₃)OR^(a);    -   R₂ is α or β and is selected from C₆H₄X, C₆H₃XY, C₁₀H₇X, and        C₁₀H₆XY;    -   R^(a) is selected from C₁-C₅ alkyl, e.g. methyl, ethyl, propyl,        isopropyl, etc.;    -   X and Y are independently selected from R^(a), H, Br, Cl, I, F,        OH, and OCH₃;

L is —(CH₂)_(n) where n is an integer from 1 to 6, or —(CH₂)_(n)-(aryl,arylalkyl, ethenyl or ethynyl)-(CH₂)_(m) where the sum of n plus m is aninteger from 1 to 6; and

-   -   Ch is a tridentate or tetradentate chelating ligand that forms a        neutral complex with technetium or rhenium,        and further wherein the bond between C₂ and C₃ is either a        single bond or a double bond.        Thus, R₁ and R₂ can be in the α or β configuration. Further, R₁        preferably can be substituted at the C₂ or C₄ when the tropane        has a 1R or 1S configuration, respectively. The chelating        ligand, if chiral, can be syn or anti with R, S, or RS.

The imaging agents of the present invention are useful for detectingtropane recognition sites including neuronal transporters such as thedopamine transporter. For purposes of the present invention, a tropanerecognition site is any receptor or transporter site that binds to thetropane compound. Thus, the compounds of this invention can be used asdiagnostic agents, prognostic agents and therapeutic agents forneurodegenerative diseases.

The present invention also provides a method of using the coordinationcomplex as an imaging agent for detecting neurodegenerative andneuropsychiatric disorders characterized by a change in density of DATor dopamine neurons. For example, a method for detecting the change inDAT resulting from a neurodegenerative disease, such as Parkinson'sdisease, comprises injecting a labeled compound of the present inventionin a dose effective amount for detecting DAT in the particular mammaland obtaining images of the labeled compound bound to DAT. Rheniumlabeled compounds can also be useful for therapeutic treatments.

The present invention also provides kits for producing the compounds ofthe present invention labeled with technetium or rhenium. The kitstypically comprise a sterile, non-pyrogenic container containinglyophilized compound and a reducing agent to form a complex of thecompound with technetium or rhenium. The kits permit readyreconstitution and labeling with aqueous solutions containing theradionuclide, e.g. pertechnetate, preferably having a pH in the range ofabout 5 to about 8.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of alternative general reaction schemes forlinking a N₂S₂ chelating ligand to a nortropane analog and labeling witha metal “M”, which can be technetium or rhenium.

FIG. 2 is an illustration of a general scheme for preparation of2-carbomethoxy tropanes (Scheme 1) comprising an aryl octene in accordwith the present invention and subsequent preparation of 3α and 3βdiasteriomers thereof.

FIGS. 3 and 4 are illustrations of a general scheme for preparation of2-ethylketo analogs (Schemes 2 and 3) of radiopharmaceutical compoundsin accord with a preferred embodiment of the present invention.

FIG. 5 is an illustration of a general scheme for preparation of2-carboxamido 3α- or 3β-aryl analogs (Scheme 4) of radiopharmaceuticalcompounds in accord with a preferred embodiment of the presentinvention.

FIG. 6 is an illustration of a general reaction scheme for preparationof 3-aryl-2-ethylketo-2,3-ene analogs (Scheme 5) of radiopharmaceuticalcompounds in accord with a preferred embodiment of the presentinvention.

FIG. 7 is an illustration of a general reaction scheme for preparationof 3-aryl-2-carbomethoxy-2,3-ene analogs (Scheme 6) ofradiopharmaceutical compounds in accord with a preferred embodiment ofthe present invention.

FIG. 8 is an illustration of a general scheme for converting the 3α and3β diasteriomers of FIG. 2 to bistrityl protected N₂S₂ tropanes andlabeling with technetium or rhenium (Scheme 7).

FIG. 9 is an illustration of an alternative general reaction scheme forpreparation of 3-aryl-2-ethylketo-2,3-ene analogs (Scheme 8) ofradiopharmaceutical compounds in accord with a preferred embodiment ofthe present invention.

FIG. 10 is an illustration of a general reaction scheme for preparationof 3-naphthyl-2-carbomethoxy-2,3-ene and 3α-naphthyl or 3β-naphthylanalogs (Scheme 9) of radiopharmaceutical compounds in accord with apreferred embodiment of the present invention.

FIG. 11 is a HPLC chromatogram of ^(99m)Tc labeled 0-1505T.

FIG. 12 is a HPLC chromatogram of ^(99m)Tc labeled 0-1508T.

FIG. 13 is a HPLC chromatogram of ^(99m)Tc labeled 0-1561T.

FIG. 14 is a HPLC chromatogram of ^(99m)Tc labeled 0-1560T.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention comprise a tropane compound orligand that selectively binds to tropane recognition sites, e.g., neurontransporters such as the DAT. The tropane ligand is radiolabeled with aradioactive technetium or rhenium by a chelating ligand which isattached to the tropane ligand by a linker. The unlabeled compounds ofthis invention are schematically represented by the formula Ch—L—Tr,wherein Ch is the chelating ligand, L is the linker and Tr is thetropane ligand.

Tropane compounds or ligands useful in the practice of the presentinvention can generally be represented by formula II where R₁ and R₂ aredefined as above and where R₁ can also be substituted at the C₄ positionof the tropane ring:

Any tropane compound of the general formula II is useful in the presentinvention so long as it binds to DAT. Examples of particularly usefultropanes are: 2-carbomethoxy-3-(4-fluorophenyl)-N-methyltropane (“WIN35,428”) (Clarke, R. L., et al., J. Med. Chem. 1973, 16, 1260-1267)which binds potently (IC₅₀=11.0 nM) and with specificity to the DAT(Meltzer, P. C., et al., J. Med. Chem. 1993, 36, 855-862);2-carbomethoxy-3-(3,4-dichlorophenyl)-N-methyltropane (“O-401”;IC₅₀=1.09 nM) (Meltzer, P. C., et al., J. Med. Chem. 1993, 36, 855-862).Tropane analogs that have a 3α-group are of the boat configuration.Other tropanes having a 3β-oriented group are of the chairconfiguration.

Chelating ligands useful in the practice of the present inventioncomprise any tridentate or tetradentate ligand that binds technetium orrhenium to form a neutral complex. The chelating ligand is covalentlyattached to the linker L, as described below. Preferred chelatingligands contain a plurality of N or S atoms for complexing with theradionuclide.

Examples of suitable ligands are the N₂S₂ compounds represented by thefollowing structural formulas:

wherein R, R⁶, and R¹⁰ are each selected from hydrogen, substituted orunsubstituted lower alkyl, alkylR⁹, or —COR⁹ where R⁹ is selected fromhydroxy, substituted lower alkoxy, substituted or unsubstituted amino,glycine ester, halide (chloro, bromo, iodo) or OR (OR is a leaving groupsuch as mesylate, triflate, or tosylate) or an activated leaving group;R¹ is selected from hydrogen, or substituted or unsubstituted loweralkyl; R² and R³ are each selected from hydrogen or a thiol protectinggroup, or an inter or intramolecular disulfide; and R⁴, R⁵, R⁷ and R⁸are each selected from hydrogen or lower alkyl.

When R, R⁶ or R¹⁰ is a carboxylic acid derivative, R⁹ can be anactivated leaving group. For purposes of this invention the leavinggroup R⁹ is defined such that (compound)-COR⁹ is an acylating agent.Examples of activated leaving groups suitable for the practice of thisinvention include, for example: halide; substituted or unsubstitutedaryloxy groups such as phenoxy, pentachlorophenoxy, etc,;oxy-heterocyclic groups such as N-oxy-succinimido, etc.; mercapto; loweralkylthio; arylthio; oxyphosphonium; and other groups known to thoseskilled in the art to be useful as leaving groups.

R² and R³ can be hydrogen or any known thiol protecting group. Examplesof such groups include lower alkylaminocarbonyl such asethylaminocarbonyl, lower alkanoylaminomethyl, aroylaminomethyl,t-butyl, acetamidomethyl, arylmethyl such as triphenylmethyl (trityl)and diphenylmethyl, aroyl such as benzoyl, aryloxycarbonyl such asphenoxycarbonyl, arylloweralkoxycarbonyl, preferablyarylmethoxycarbonyl, benzyloxycarbonyl, and lower alkoxycarbonyl such ast-butoxycarbonyl. Preferred thiol protecting groups include trityl,t-butyl, diphenylmethyl, acetamidomethyl and benzoyl and an inter orintramolecular disulfide.

The term “lower alkyl” when used herein designates aliphatic saturatedbranched or straight chain hydrocarbon monovalent substituentscontaining from 1 to 6 carbon atoms such as methyl, ethyl, isopropyl,n-propyl, n-butyl, etc., more preferably 1 to 4 carbons. The term “loweralkoxy” designates lower alkoxy substituents containing from 1 to 6carbon atoms such as methoxy, ethoxy, isopropoxy, etc., more preferably1 to 4 carbon atoms.

The terms substituted lower alkyl or substituted lower alkoxy when usedherein include alkyl and alkoxy groups substituted with halide, hydroxy,carboxylic acid, or carboxamide groups, etc. such as, for example,—CH₂OH, —CH₂CH₂COOH, —CH₂CONH₂, —OCH₂CH₂OH, —OCH₂COOH, —OCH₂CH₂CONH₂,etc.

The term substituted amino when used herein includes such groups mono ordi and tri-substituted with lower alkyl, and —NH₃ ⁺ or mono, di andtri-substituted ammonium groups substituted with lower alkyl with apharmacologically suitable anion.

The term glycine ester as used herein means the lower alkyl esters ofglycine, preferably the methyl and ethyl esters.

These chelating ligands can be complexed with a radionuclide, e.g.,technetium, to form the following complexes:

where the R groups are defined as above.

Preferred embodiments of the invention use chelating ligands that areformed from monoaminomonoamide compounds having structures of formula V,VI or VII, e.g.,N-{2-((2-((triphenylmethyl)-thio)-ethyl)amino)acetyl}-S-(triphenylmethyl)-2-aminoethanethiol(“MAMA′”).

Any organic linker having a backbone chain length of 1 to about 6 carbonatoms can be used to attach the chelating ligand, typically through itsnitrogen, sulfur, R, R¹ or R⁶, to the 8-nitrogen atom of the tropaneligand (which binds the dopamine transporter). Examples of linkersinclude —(CH₂)_(n) where n is an integer from 1 to 6, or—(CH₂)_(n)-(aryl, arylalkyl, ethenyl or ethynyl)-(CH₂)_(m) where the sumof n plus m is an integer from 1 to 6.

Preferred radiolabeled compounds of the present invention cross theblood brain barrier and exhibit desired target:non-target specificity.Preferably, the selectivity ratio of binding (DAT:SET) is about 30 ormore, more preferebly 50 or more. Thus, they are useful as brain imagingagents, for example, for imaging DAT.

The tropane ligands can be linked to the chelating ligand by an initialconversion to nortropanes. Syntheses of nortropanes are known in theart, for example, as disclosed in Meltzer, P. C., et al., J. Med. Chem.1993, 36, 855-862; Meltzer, P. C., et al., J. Med. Chem. 1994, 37,2001-2010 (the disclosure of which is incorporated herein by reference).Tropanes can be synthesized from tropinone or cocaine by techniquesknown in the art. Synthesis of the nortropanes can then be achieved byN-demethylation of the tropane, which can be readily accomplished byvarious methods known in the art, e.g., with α-chloroethyl chloroformate (ACE-Cl).

The chelating ligand is preferably prepared separately and, then, eitherattached to the nortropane and metallated, or metallated first followedby attachment to the appropriate nortropane. When the radiolabeledcompounds of the invention are required to cross the blood brainbarrier, the chelating ligands useful in the present invention formneutral complexes with the radionuclide and are lipid soluble. Chelatingligands that form neutral ^(99m)Tc(V) complexes which are useful in thepresent invention include a substituted oxime (Loberg, M. D., et al., J.Nucl. Med. 1979, 20, 1181-1188), N₂S₂ compounds (Davison, A., et al.,Inorg. Chem. 1981, 20, 1629-1632; Davison, A., et al., J. Nucl. Med.1979, 20, 641 (abstr)), bisaminoethanethiol (“BAT”) (Kung, H. F., etal., J. Med. Chem. 1985, 28, 1280-1284; Kung, H. F., et al., J. Nucl.Med. 1986, 27, 1051; Kung, H. F., et al., J. Med. Chem. 1989, 32,433-437; Kung, H. F., et al., J. Nucl. Med. 1984, 25, 326-332;Francesconi, L. C., et al., Inorg. Chem. 1993, 32, 3114-3124), anddiaminodithiol (“DADT”) (Lever, S. Z., et al., J. Nucl. Med. 1985, 26,1287-1294). Additional examples of useful chelating ligands includeN,N′-bis(2-mercapto-1-methyl)-2-aminobenzylamine (“U-BAT”) (Francesconi,L. C., et al., J. Med. Chem. 1994, 37, 3282-3288), propylene amineoximes (“HMPAO”), diamidodithiol (“DADS”) (Rao, T. N., et al., J. Am.Chem. Soc. 1990, 112, 5798-5804; Stepniak-Biniakiewicz, D., et al., J.Med. Chem. 1992, 35, 274-279), phenylenediamine-thiol-thioether (“PhAT”)(McBride, B. J., et al., J. Med. Chem. 1993, 36, 81-86),bis(mercaptoethyl)-2-aminoethylamine (“SNS”) orbis(mercaptoethyl)-2-thioethylamine (Mastrostamatis, S. G., et al., J.Med. Chem. 1994, 37, 3212-3218), monoamine amide (“MAMA”) (Gustavson, L.M., et al., Tet. Lett. 1991, 32, 5485-5488) andN-{2-((2-((triphenylmethyl)thio)ethyl)amino)acetyl}-S-(triphenylmethyl)-2-aminoethanethiol(“MAMA”′) (O'Neil, J. P., et al., Inorg. Chem. 1994, 33, 319-323). Forexample, when MAMA′ is attached to a lipophilic tropane by a linker inaccord with the present invention, a neutral, moderately lipophilic andaqueous stable compound suitable for radiolabeling is formed.

Compounds of formula III and IV can be synthesized according to themethods described in U.S. Pat. No. 4,673,562 which is incorporatedherein by reference. Compounds of formula V can be synthesized bymethods known in the art (see Fritzberg et al., J. Nucl. Med. 1981, 22,258-263). Compounds of formula VI can also be synthesized by methodsknown in the art. (See O'Neil, J. P., et al., Inorg. Chem. 1994, 33,319-323).

Radiolabeled complexes of the present invention can be prepared viathree general preparation procedures as outlined in the General Scheme(FIG. 1). The general preparation scheme exemplifies the use of tritylprotecting groups for the sulfhydryls, however, other protecting groupsthat are known to be useful for sulfhydryl protection can also be usedsuch as, for example, lower alkylaminocarbonyl such asethylaminocarbonyl, lower alkanoylaminomethyl, arylaminomethyl, t-butyl,acetamidomethyl, arylmethyl such as triphenylmethyl(trityl) anddiphenylmethyl, aryl such as benzoyl, aryloxycarbonyl such asphenoxycarbonyl, aryl loweralkoxycarbonyl, preferablyarylmethoxycarbonyl such as benzyloxycarbonyl, and lower alkoxycarbonylsuch as t-butoxycarbonyl. Preferred sulfhydryl protecting groups includetrityl, t-butyl, diphenylmethyl, acetamidomethyl, disulfide and benzoyl.

The compounds of the invention can be prepared by known means based uponthe present disclosure. For example, starting with an appropriatechelating ligand, such as an N₂S₂ compound, illustrated in the generalscheme in FIG. 1 asN-{2-((2-((triphenylmethyl)thio)ethyl)amino)acetyl}-S-(triphenylmethyl)-2-aminoethanethiol,(MAMA′: Katzenellenbogen et al., Inorg. Chem., 1994, 33, 319), the N₂S₂compound can be alkylated with either the haloalkyl triflate or thehaloalkylnortropane (prepared from the nortropane: Meltzer et al., J.Med. Chem., 1993, 36, 855), producing the chloroalkyl (propyl shown)MAMA′, or the tropanalkyl (propyl shown) MAMA′, compounds, respectively.The chloroalkyl (propyl shown) MAMA′ compound, can then be attached to asuitable nortropane to provide the tropanalkyl (propyl shown) MAMA′compounds, as shown. Alternatively, the chloroalkyl (propyl shown)MAMA′, can be treated to incorporate a metal atom, preferably aradionuclide (such as ⁹⁹Tc, ^(99m)Tc, ¹⁸⁸Re or ¹⁸⁶Re) to provide theM-labeled complex. The resulting complex can then be attached to asuitable nortropane to provide radiopharmaceutical compounds of thepresent invention, as shown.

Alternatively, the tropanalkyl (propyl shown) MAMA′ compounds, can betreated to incorporate a radionuclide (such as ⁹⁹Tc, ^(99m)Tc, ¹⁸⁸Re or¹⁸⁶Re) to form radiopharmaceutical compounds of the present invention,as shown.

The compounds of the present invention can be either diastereoisomer aswell as a mixture of both diastereomers. The diastereoisomers can beseparated by column chromatography.

More specifically, alkylation of the N₂S₂, with haloalkyl triflate toproduce the chloroalkyl (propyl shown) MAMA′, can be used to prepare thelinker which is used to bind the chelating ligand to the tropane ligand,which selectively binds the dopamine transporter. This alkylation stepcan be modified by those of ordinary skill in organic chemistry tocreate various linkers having a backbone chain length of 1 to about 6carbon atoms, as described above.

Deprotection of the chloroalkyl compound can be accomplished by standardmethods well known in the art, e.g., with H₂S/Hg(OAc)₂ (O'Neil, J. P.,et al., Inorg. Chem. 1994, 33, 319-323) or AgNO₃/Py (DiZio, J. P., etal., Bioconj. Chem. 1991, 2, 353-366), with TFA and phenol, or HBr inacetic acid (Zervas, L., et al., J. Amer. Chem. Soc. 1962, 84,3887-3897) to result in the unprotected bisthiol which can then beimmediately treated with a solution of tin (II) chloride (SnCl₂) andsodium perrhenate (Na₂ReO₇) or an agent such as Na(^(99m)TcO₄)/stannoustartrate (Francesconi, L. C., et al., Inorg. Chem. 1993, 32, 3114-3124;Canney, D. J., et al., J. Med. Chem. 1993, 36, 1032-1040) to produce thelabeled complexes. Purification of these chelates can be accomplished byflash chromatography as described by O'Neil (O'Neil, J. P., et al.,Inorg. Chem. 1994, 33, 319-323). The chloroalkyl chelate, can then bereacted (O'Neil, J. P., et al., Bioconj. Chem. 1994, 5, 182-193) withthe appropriate nortropane to provide the labeled coordination complexesof the present invention. Alkylation of nortropanes can be accomplishedby methods known in the art, e.g., acetonitrile (CH₃CN), potassiumiodide (KI) and potassium carbonate (K₂CO₃). The use of strong base cancause epimerization of the carbomethoxy group at C-2, although sodiumcarbonate in a solvent such as dimethyl formamide (DMF) can yieldalkylated products in reasonable yield.

These compounds can be prepared either as free bases or as apharmacologically active salt thereof such as hydrochloride, tartrate,sulfate, naphthalene-1,5-disulfonate or the like.

Reaction schemes for preparation of various classes of compounds of thepresent invention are described with reference to the drawings. InScheme 1, as illustrated in FIG. 2, Keto ester 1 {Meltzer et al., J.Med. Chem, 1994, 37, 2001} is converted to the enol triflate 2 byreaction with N-phenyltrifluoromethanesulfonimide and sodiumbis(trimethylsilyl)amide in tetrahydrofuran. The enol triflate 2 is thencoupled with the appropriate commercial or preformed arylboronic acidsby Suzuki coupling in diethoxymethane in the presence of lithiumchloride, sodium carbonate and tris(dibenzylideneacetone)dipalladium(0)to provide aryl octenes 3 in excellent yield.

Reduction of the octenes 3 with samarium iodide intetrahydrofuran/methanol at low temperature (−78° C.) provides a mixtureof the 3β- and 3α-diastereomers, 4 and 12 respectively. Thesediastereomers are readily separated by flash column chromatography.

In Scheme 7, as illustrated in FIG. 8, the 3β- and 3α-diastereomers 4and 12 are then treated similarly in their conversion to the bistritylprotected N₂S₂ tropanes 33 and 36 respectively and thence to the rheniumanalogs 34R and 37R and the technetium analogs 34T and 37T. Thus, thetropanes are N-dealkylated by treatment with ACE-chloride {Meltzer etal., J. Med. Chem, 1993, 36, 855} to provide the nortropanes 32 and 35.Introduction of the N₂S₂ protected, ligand is then achieved by reactionof the nortropanes with the preformedN-[[[2-[2-(triphenylmethyl)thio]ethyl](N′-3′-chloropropyl)amino]acetyl]-S-(triphenylmethyl)-2-aminoethanethiol (MAMA′-Cl){Meltzer et al. J. Med. Chem., 40, 1835,1997} in the presence of potassium iodide and potassium carbonate.Rhenium can then be introduced upon reaction with tin (II) chloride in0.05 M HCl, followed by sodium perrhenate in 0.05 M HCl. The product ispurified by silica gel column chromatography and obtained as a mixtureof diastereomers. An alternative approach utilizes N-alkylation of thenortropanes with preformed N-[(2-((3′-chloropropyl)(2-mercaptoethyl)amino)acetyl)-2-aminoethane-thiolato]rhenium (V) oxide{Meltzer et al. J. Med. Chem., 40, 1835, 1997}. Both diastereomers ofthe metal chelate are prepared.

In Schemes 2 and 3, as illustrated in FIGS. 3 and 4, the 2-ethylketoanalogs in both the 3α- and 3β-series are prepared as shown. Thisdiscussion exemplifies the 3β-diastereomer, as illustrated in FIG. 3.The 3β-diastereomer 4 is hydrolyzed in dioxane/water or with lithiumhydroxide to provide the acid, 5 which is converted to the amide throughconversion to the acid chloride with oxalyl chloride and then reactionwith (MeO)MeNH.HCl to provide 6. Further reaction with alkyl Grignard atlow temperature provides the desired ethyl or alkyl ketone 7. The alkylketone 7 can be made alternatively by reaction of the ester-tropane (4or 12) with the appropriate alkyl-Grignard-(ethylmagnesium bromide inthis case) (Ref: I. Kikkawa and T. Vorifuji, Synthesis (1980), p. 877).Demethylation is by standard treatment with ACE-Cl to obtain 8. Thechelating unit is attached by reaction of 8 with MAMA′-Cl in thepresence of a base such as potassium carbonate or potassium bicarbonateand potassium iodide. Insertion of rhenium to provide 10 or technetiumto provide 11 is accomplished with sodium perrhenate under reductiveconditions, of the technetium heptogluconate. Both diastereomers of themetal chelate can be prepared in a similar manner. As seen by comparingSchemes 2 and 3, the 3α-diastereomer of the tropane is prepared in asimilar manner.

In Scheme 4, as illustrated in FIG. 5, the 2-carboxamide analogs 22 and22A are prepared from 14 by N-demethylation with ACE-Cl as describedearlier.

Attachment of the MAMA′ group and insertion of the metal (rhenium ortechnetium) is conducted as described earlier for Schemes 2 and 3.

In Scheme 5, as illustrated in FIG. 6, the 2-ethylketo trop-2-eneanalogs are prepared as shown in the scheme. Thus, ester 3 is hydrolyzedin dioxane/water or with lithium hydroxide to provide the acid 23 whichis converted to the amide through conversion to the acid chloride withoxalyl chloride and then reaction with (MeO)MeNH.HCl to provide 24.Further reaction with alkyl Grignard at low temperature provides thedesired ethyl or alkyl ketone 25. The alkyl ketone 25 can be formedaltneratively by reaction of the ester tropene (3) with the appropriatealkyl-Grignard-(ethylmagnesium bromide) (Ref: I. Kikkawa and T.Vorifuji, Synthesis (1980), p. 877). Demethylation is by standardtreatment with ACE-Cl to obtain 26. The chelating unit is attached byreaction of 26 with MAMA′-Cl in the presence of a base such as potassiumcarbonate or potassium bicarbonate and potassium iodide. Insertion ofrhenium or technetium to provide 28 is accomplished with sodiumperrhenate under reductive conditions of the technetium heptogluconate.Both diastereomers of the metal chelate 28 are prepared.

In Scheme 6, as illustrated in FIG. 7, the 2-carbomethoxy trop-2-eneanalogs are prepared as shown in the scheme. Demethylation of compound 3is by standard treatment with ACE-Cl to obtain compound 29. Thechelating unit is attached by reaction of compound 30 with MAMA′-Cl inthe presence of a base such as potassium carbonate or potassiumbicarbonate and potassium iodide. Insertion of rhenium or technetium toprovide compound 31 is accomplished with sodium perrhenate underreductive conditions, of the technetium heptogluconate. Bothdiastereomers of the metal chelate 31 are prepared.

In Scheme 8, as illustrated in FIG. 9, the 2-ethylketo trop-2-eneanalogs are prepared as shown in the scheme. Thus, compound 3 is reducedwith LAH and reoxidized to obtain the aldehyde 39. Reaction of thealdehyde with ethyl lithium or ethyl Grignard provides the alcohol 40which is oxidized once again to obtain the ethyl ketone 26. Compounds 27and 28 are then obtained as above.

In Scheme 9, as illustrated in FIG. 10, the 3-naphthyl trop-2-ene and3α-and 3β-tropanes are obtained by similar chemistry to that describedearlier. Thus, the trop-2-ene 38 is N-demethylated with ACE-Cl and theMAMA′ is attached to provide compound 40. Rhenium or technetium areinserted as before to obtain the diastereomers 41. Alternatively,compound 38 is first reduced with samarium iodide to obtain both theboat and chair configured compounds 43 and 42. The same sequence ofreactions then provides the rhenium and technetium diastereomers of boththe 3α- and 3β-tropanes, 49 and 48.

The technetium or rhenium radionuclide complexes of this invention canbe formed by reacting suitable precursor compounds with eitherpertechnetate or perrhenate in the presence of a suitable reducing agentin a conventional manner. For example, the compound can be dissolved ina suitable solvent with a reducing agent and then pertechnetate added.The mixture is then heated for a suitable length of time to complete thereaction. Typically, heating in a boiling water bath for about 10minutes has been found sufficient to obtain very good yields of theradionuclide complex. To form rhenium complexes, (Ph₃P)₂ReOCl₃ is addedin the presence of basic (NaOAc) methanol. Examples of reducing agentsuseful in the practice of this invention include stannous salts such asstannous chloride, sodium dithionite, and ferrous salts such as ferroussulfate.

Rhenium behaves similarly to Tc. Thus, N₂S₂ complexes of Re or Tc areequally stable. Both metals form square pyramidal complexes with N₂S₂ligands. (Francesconi, L. C., et al., Inorg. Chem. 1993, 32, 3114-3124).Rhenium is a preferred metal for use in studies which do not require thepresence of a short half life radiolabel. For complexes with bothtechnetium and rhenium, the oxygen occupies an apical position,therefore both syn and anti-isomers of the metal complexes are possible.The biological activity of Tc and Re chelates are generally similar.(O'Neil, J. P., et al., Bioconjugate Chem. 1994, 5, 182-193). ^(99m)Tcis a preferred radionuclide for use as an imaging agent. Rhenium is anexcellent model for ^(99m)Tc and is also useful as a therapeutic agent.

A preferred method for introducing the technetium radionuclide was byreaction of the bistrtityl protected compounds in presence of anhydroustrifluoroacetic acid and then triethylsilane. A portion of the aqueoussolution thus obtained was then incubated with ^(99m)Tc-glucoheptonatesolution (Glucoscan kits from Du Pont, Billerica, Mass.). HPLCseparation on a C₈ reverse phase column equipped provides the major^(99m)Tc labeled product which was reconstituted in sterile saline forinjection.

The compounds of this invention are typically enantiomerically puretropanes (either 1S or 1R configuration) attached by an achiral linkerto a chiral chelating ligand. The chiral chelating ligand can be cis ortrans with respect to the metal oxo and the linker, but is preferablycis. Each of the cis and trans chelating ligands exist as a pair of twoenantiomers. By virtue of the chiral ligand which can exist in each oftwo enantiomeric forms, and a chiral tropane, each of the wholemolecules exists as diastereoisomers. Radiopharmaceutical compositionsof the present invention include the separate diastereoisomers of each,as well as mixtures of diastereomeric pairs.

The compounds of the present invention preferably have atarget:nontarget ratio, such as a DAT:SET selectivity ratio of greaterthan 10, and preferably at least 30, to minimize binding of trace levelsof the drug to the nontarget, e.g., serotonin transporter.

The present invention also provides pharmaceutical kits, preferablycomprising the compounds of formula I with a reducing agent inlyophilized form in a pyrogen-free, sterilized container or vial. Inthis form the lyophilized composition can be readily reconstituted byadding only water, saline, or a buffer preferably having a pH in therange of 5 to 8, more preferably physiological pH. If technetium is themetal to be used as the radionuclide, pertechnetate solution from atechnetium generator can be used for reconstitution.

In general, the radiopharmaceutical preparation kit comprises asterilized unit dose (or multidose) vial containing the purifiedcompound of formula I and a reducing agent for technetium, preferablylyophilized. Each dose should consist of a sufficient amount of compoundand reducing agent to prepare the required dose for imaging, normallyabout 5 to about 30 mCi of ^(99m)Tc depending upon body weight of themammal to be imaged. In use, the technetium, preferably as^(99m)Tc-pertechnetate in saline, is injected aseptically into the vialand the mixture reacted for a sufficient time to form the labeledcomplex. After reaction, typically, the resulting radiopharmaceutical isready for use.

To image a desired target, a radiopharmaceutical preparation in accordwith this invention having an effective dose of radioactivity for theparticular mammal is prepared in a suitable pharmacological carrier,such as normal saline. Preferably, the radiopharmaceutical preparationis injected intravenously into the mammal. The target, e.g., the brain,is then imaged by positioning the mammal under a gamma camera or othersuitable device.

In order to obtain high quality images, the radiochemical yield of boundtechnetium in the desired radiopharmaceutical should preferably begreater than 70% after reconstituting the lyophilized mixture andlabelling. Lower yields may result in poorer image quality andundesirable purification steps may be required to produce high qualityimages.

This invention will be illustrated further by the following examples.These examples are not intended to limit the scope of the claimedinvention in any manner.

The final compounds were characterized and their purity analyzed priorto biological evaluation. High field nuclear magnetic resonance (NMR)spectra were measured as well as low and high resolution mass spectra(MS) and infrared spectra (IR). Elemental analyses, thin layerchromatography (TLC) and/or high performance liquid chromatography(HPLC) were used as a measure of purity. A purity of >98% was obtainedbefore biological evaluation of these compounds was undertaken.

In the following examples, NMR spectra were recorded on either a Bruker100, a Varian XL 400, or a Bruker 300, or a Jeol 300 NMR spectrometer.TMS was used as internal standard. Melting points are uncorrected andwere measured on a Gallenkamp melting point apparatus. Optical rotationswere measured at the sodium D line at 21° C. using a JASCO DIP 320polarimeter (1 dcm cell). Thin layer chromatography (TLC) was carriedout on Baker Si 250F plates. Visualization was accomplished with eitheriodine vapor, UV exposure or treatment with phosphomolybdic acid (PMA).Preparative TLC was carried out on Analtech uniplates Silica Gel GF 2000microns. Flash chromatography was carried out on Baker Silica Gel 40 M(SiO₂). Elemental Analyses were performed by Atlantic Microlab, Atlanta,Ga. A Beckman 1801 Scintillation Counter was used for scintillationspectrometry. 0.1% Bovine Serum Albumin and (−)-Cocaine were purchasedfrom Sigma Chemicals. All reactions were conducted under an atmosphereof dry nitrogen.

[³H]WIN 35,428 and2β-carbomethoxy-3β-(4-fluorophenyl)-N-[³H]methyltropane (79.4-87.0Ci/mmol), and [³H]citalopram (86.8 Ci/mmol) were purchased fromDuPont-New England Nuclear (Boston, Mass.). TEA is triethylamine.(−)-Cocaine hydrochloride for the pharmacological studies was donated bythe National Institute on Drug Abuse [NIDA]. Fluoxetine was donated byE. Lilly & Co. HPLC analyses were carried out on a Waters 510 systemwith detection at 254 nm on a Waters 8 mm, C-18, 10 m reverse phasecolumn. Pd₂dba₃ is trisdibenzylideneacetone dipalladium, TFA istrifluoroacetic acid, THF is tetrahydrofuran, EtOAc is ethyl acetate.

EXAMPLE 1(1R)-2-(Methoxycarbonyl)-3-[[(trifluoromethyl)sulfonyl]oxy]trop-2-ene(Compound 2, FIG. 2)

(1R)-(−)-2-Methoxycarbonyl-3-tropinone, 1 {Meltzer et al., J. Med. Chem,1994, 37, 2001} (1 g, 5.07 mmol) was dissolved in anhydrous THF (20 mL)and the resulting solution cooled to −78° C. A solution of sodiumbistrimethylsilylamide (1 M, 5.58 mL, 5.58 mmol) was then added to thesolution slowly. After 30 min, N-phenyltrifluoromethane sulfonamide(1.94 g, 5.43 mmol) was added. The resulting solution stirred for afurther 45 min at −78° C. and then allowed to attain room temperatureand stirred at room temperature for 2 h. All solvent was evaporated andthe residue pumped to dryness. Column chromatography was performed onthe residue (SiO₂ 60 g; 2%-16% methanol in ethyl acetate) and gave 1.62g (97%) of a yellow oil which crystallized on standing.

R_(f) 0.65 (10% MeOH/EtOAc). ¹H-NMR (CDCl₃) δ 1.58 (m, 1H), 1.97 (m,2H), 2.1-2.2 (m, 2H), 2.39 (s, 3H). 2.84 (dd, J=18, 4 Hz, 1H), 3.42 (t,J=6 Hz, 1 H), 3.8 (s, 3H), 3.92 (d, J=5 Hz, 1H).

EXAMPLE 2(1R)-N-Methyl-2-methoxycarbonyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene(Compound 3, FIG. 2)

(1R)-2-Methoxycarbonyl-3-[[(trifluoromethyl)sulfonyl]oxy] tropene 2 (620mg, 1.88 mmol), LiCl (171 mg, 4.03 mmol), Pd₂dba₃ (69 mg, 0.075 mmol),aq. Na₂CO₃ (2.0 M, 2 mL), diethoxymethane (6.2 mL) were all charged to aflask and stirred vigorously. To this solution was added3,4-dichlorophenyl boronic acid (474 mg, 2.49 mmol). The reaction wasthen brought to reflux for 2 h and filtered through celite. The cake waswashed with ether and the organic solution was washed with concentratedNH₄OH. The washed solvent was dried with K₂CO₃, filtered, andevaporated. The residue was charged to a column (SiO₂, 60 g, eluted with5-6% Et₃N/EtOAc) and gave 512 mg (83%) of a yellow oil which solidifiedupon standing.

R_(f) 0.56 (10% Et₃N/EtOAc). IR (KBr) 2941, 1724, 1460, 1418, 1333,1250, 1212, 1124 cm⁻¹. ¹H-NMR (CDCl₃) δ 1.61 (m, 1H), 1.9-2.05 (m, 2H),2.1-2.3 (m, 2H), 2.43 (s, 3H), 2.76 (dd, J=19, 4.7 Hz, 1H), 3.36 (t,J=4.9 Hz, 1H), 3.52 (s, 3H), 3.86 (d, J=5.5 Hz, 1H), 6.96 (dd, J=8.3,1.9 Hz, 1H), 7.2 (d, J=2.2 Hz, 1H), 7.37 (d, J=8.2 Hz, 1H). Elementalanalysis: calculated C, 58.91; H, 5.25; N, 4.29; found C, 58.84; H,5.24; N, 4.24.

EXAMPLE 3(1R)-N-Methyl-2β-methoxycarbonyl-3β-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane(Compound 4 (R=3,4-Cl₂), FIG. 2), and(1R)-N-Methyl-2β-methoxycarbonyl-3α-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane(Compound 12 (R=3,4-Cl₂), FIG. 2)

To(1R)-N-Methyl-2-methoxycarbonyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene,3 (4 g, 12.3 mmol) in THF (43 mL) at −78° C. was added SmI₂ solution(0.1 M in THF, 400 mL, 40 mmol) dropwise. After 30 min at −78° C., MeOH(140 mL) was added and the resulting solution stirred at −78° C. for afurther 1 h. The reaction was then quenched with TFA (28 mL) and water(285 mL), the cold bath was removed and the solution allowed to attainroom temperature. The reaction was then made basic with NH₄OH anddiluted with ether and filtered through celite. The filter cake waswashed with ether and all the organic phases were combined and washedwith a sodium thiosulfate solution and then a brine solution. Afterdrying with Na₂SO₄ the solution was filtered and concentrated and gave3.8 g of the crude products. The title compounds 4 and 12 were isolatedby column chromatography (SiO₂, 10 g; 2.5% EtOH in CHCl₃). Compound 12was isolated as colorless crystals (1.15 g, 29%).

Mp. 89-91° C. R_(f) 0.64 (1% NH₄OH/EtOAc). ¹H-NMR (CDCl₃) δ 1.28 (ddd,J=1.6, 10.4, 14, 1H), 1.4-1.6 (m, 2H), 2.23 (s, 3H), 2.05-2.3 (m, 2H),2.35-2.5 (m, 2H), 3.2-3.47 (m, 3H), 3.59 (s, 3H), 7.04 (dd, J=2.2, 8.2Hz, 1H), 7.27 (d, J=2.2 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H). Elementalanalysis: calculated (0.1 C₆H₁₄) C, 59.18; H, 6.10; N, 4.16; Cl, 21.05;found C, 59.11; H, 5.90; N, 4.08; Cl, 21.01.

Compound 4 (R=3,4-Cl₂) (Meltzer et al., J. Med. Chem., 1993, 36,855-862) was isolated as a yellow solid (1.04 g, 26%).

Mp. 82.5-83.5° C. R_(f) 0.43 (IPA/Et₂O/pentane; 3/30/67); ¹H NMR (400MHz, CDCl₃) δ 1.6-1.7 (m, 3H), 2.0-2.1 (m, 2H), 2.21 (s, 3H), 2.50 (ddd,1H, H-4), 2.86 (m, 1H), 2.92 (m, 1H), 3.33 (m, 1H, H-5), 3.52 (s, 3H),3.55 (m, 1H), 7.07-7.32 (m, 3H). [α]_(D) ²¹−27.0° (c=1, CH₃OH). Anal.(C₁₆H₁₉NO₂Cl₂) C, H, N, Cl.

EXAMPLE 4(1R)-N-Methyl-2β-methoxycarbonyl-3β-(4-fluorophenyl)-8-azabicyclo[3.2.1]octane(Compound 4 (R=4-F), FIG. 2) and(1R)-N-Methyl-2β-methoxycarbonyl-3α-(4-fluorophenyl)-8-azabicyclo[3.2.1]octane(Compound 12 (R=4-F), FIG. 2; O-1204)

Using the same general procedure as described above for Example 3,except substituting(1R)-N-Methyl-2-methoxycarbonyl-3-(4-fluorophenyl)-8-azabicyclo[3.2.1]oct-2-ene,3, compounds 4 and 12 (R=4-F) were obtained.

Compound 4 (R=4-F): white solid; Mp 93-94° C.;

R_(f) 0.42 (i-PrNH₂:Et₂O:pentane::5:30:65); ¹H-NMR (400 MHz, CDCl₃) δ1.57-1.75 (m, 3H), 2.0-2.2 (m, 2H), 2.23 (s, 3H), 2.54 (ddd, 1H), 2.84(t, 1H), 2.95 (ddd 1H, J=5.3, 12.7 Hz), 3.36 (m, 1H), 3.50 (s, 3H), 3.55(m, 1H), 6.9-7.25 (m, 4H). [α]_(D) ²¹−45.6° (c=1, CH₃OH). Anal.(C₁₆H₂₀NO₂F) C, H, N.

Compound 12 (R=4-F): colorless oil;

R_(f) 0.5 (10% MeOH in EtOAc); Elemental analysis: calculated C, 69.29;H, 7.27; N, 5.05; found C, 69.35; H, 7.26; N, 5.00; IR 2900, 1750, 1500cm−1, ¹H-NMR (100 MHz, CDCl₃) δ 1.1-1.8 (m, 4H), 1.9-2.6 (m, 3H), 2.25(s, 3H), 3.1-3.7 (m, 3H), 3.59 (s, 3H), 6.8-7.3 (m, 4H).

EXAMPLE 5 2β-Carboxy-3β-(4-fluorophenyl)tropane (Compound 5 (R=4-F),FIG. 3)

2β-Methoxycarbonyl-3β-(4-fluorophenyl)tropane (WIN 35,428), 4 (1.25 g,4.54 mmol) was refluxed for 24 h in a 1:1 dioxane-water (80 mL)solution. The solvent was removed in vacuo and the residue was almostcompletely dissolved in CHCl₃ (275 mL). Remaining undissolved solid wasfiltered off, toluene (30 mL) was added, and the solution was reduced invacuo by approximately 75%. After cooling the resulting white suspensionin the freezer for 2 h, the white solid was removed by filtration andwas washed with cold 1:1 CHCl₃-toluene. The solid was pumped dry toyield the product 5 as a white solid (1.11 g, 95%).

¹H-NMR (CDCl₃) δ 1.7-1.8 (m, 1H), 1.94 (dd, J=9 Hz, 2H) 2.24-2.34 (m,2H), 2.25 (m, 3H), 2.57 (ddd, J=13.7 Hz, 1H), 2.62-2.68 (m, 1H), 3.16(ddd, J=13 Hz, 1H), 3.5-3.6 (m, 2H), 6.8 (m, 2H), 7.18-7.24 (m, 2H).

EXAMPLE 6 2β-Carboxy-3β-(3,4-dichlorophenyl)tropane (Compound 5(R=3,4-Cl₂), FIG. 3)

2β-Methoxycarbonyl-3β-(3,4-dichlorophenyl)tropane, 4 (1.14 g, 3.47 mmol)was dissolved in THF:MeOH (1:1; 46 mL) to which was added a solution ofLiOH.H₂O (153 mg) in water (11 mL). The solution was heated to refluxfor 24 h, cooled to 0° C. and neutralized (pH=7) with conc. HCl. Silica(1.75 g) was added directly to the solution and solvent was removed invacuo. The material was purified by flash chromatography column (eluent20% MeOH/CHCl₃ (900 mL) followed by 30% MeOH/CHCl₃ (2 L)). Fractionscontaining the product were collected and combined, evaporated in vacuoand the residue was dried at high vacuum. The product was obtained (310mg; 28%).

R_(f) 0.08 (30% MeOH/CHCl₃); ¹H-NMR (CDCl₃) δ 1.8-1.9 (m, 1H), 2.1-2.2(m, 2H) 2.3-2.5 (m, 2H), 2.6-2.9 (m, 2H), 2.78 (s, 3H), 3.3-3.4 (m, 1H),3.93 (m, 2H), 7.25 (dd, J=8.2 Hz, 2.2 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H),7.48 (d, J=2.2 Hz, 1H).

EXAMPLE 7 2β- Methoxymethylcarbamoyl-3β-(4-fluorophenyl)tropane(Compound 6 (R=4-F), FIG. 3)

To a stirred suspension of the acid 5 (1.1 g) in anhydrous CH₂Cl₂ (80mL) containing DMF (50 μL) was added oxalyl chloride (1 mL, 11.4 mmol)dropwise resulting in copious bubbling and dissolution of thesuspension. The reaction was allowed to stir for 45 min during whichtime the solution became yellow. The solution was then reduced in vacuoand pumped at high vacuum overnight, care being taken to bleed nitrogeninto the evacuated flask when transferring from the rotary to the pump.

To the acid chloride dissolved in CH₂Cl₂ (80 mL) was added (MeO)MeNH HCl(450 mg; dried immediately prior to use over P₂O₅ under high vacuumfollowed immediately by pyridine (1.1 mL). The reaction was allowed tostir for 1 h and was partitioned across CHCl₃ (20 mL) and 2M Na₂CO₃ (20mL). The aqueous layer was extracted CHCl₃ (2×10 mL) and the combinedorganic extracts were dried over Na₂SO₄, filtered and reduced in vacuoto yield 1.09 g of a yellow solid. The crude product was dissolved inCH₂Cl₂ and purified by flash chromatography (SiO₂, 43 g; 20%hexanes/EtOAc, 5% Et₃N). Product containing fractions were combined andconcentrated to yield a light yellow solid 6 (960 mg; 75%).

Mp. 120.1-122.5° C.; R_(f) 0.14 (25% hexanes/EtOAc, 5% TEA); Elementalanalysis: calculated C, 66.65; H, 7.57; N, 9.14; found C, 66.78; H,7.63; N, 9.01; IR (KBr) 2900, 1680, 1500 cm⁻¹; ¹H-NMR (CDCl₃) δ 1.5-1.8(m, 3H), 2.0-2.3 (m, 2H), 2.24 (m, 3H), 2.79 (ddd, 1H), 3.0 (m, 1H),3.05 (s, 3H), 3.1 (m, 1H), 3.4 (m, 1H), 3.47 (m, 1H), 3.57 (s, 3H), 6.9(m, 2H), 7.25 (m, 2H).

EXAMPLE 8 2β-Methoxymethylcarbamoyl-3β-(3,4-dichlorophenyl)tropane(Compound 6 (R=3,4-Cl₂), FIG. 3)

To a stirred solution of 2β-carboxy-3β-(3,4-dichlorophenyl)tropane, 5(300 mg, 9.55 mmol) in anh. CH₂Cl₂ (30 mL) was added anh. DMF (40 μL)and oxalyl chloride (450 μL) dropwise. The solution was stirred at roomtemperature for 40 min. The solvent was removed in vacuo and the residuedried at high vacuum overnight.

To the dry residue was added methoxy methylamine hydrochloride (103 mg,1.05 mmol). The flask was flushed with nitrogen and CH₂Cl₂ (30 mL) wasadded by cannula followed immediately by pyridine (400 μL). The reactionwas stirred for 2.5 h. The resultant mixture was partitioned betweenCH₂Cl₂ (40 mL) and 1M Na₂CO₃ (25 mL). The aqueous layer was extractedwith CHCl₃ and the combined organic extracts were dried and concentratedto yield a yellow solid (298 mg). The solid was purified on achromatography column (eluent 50% EtOAc/hexane/5% Et₃N). Like fractionswere combined, solvent removed and the product dried at high vacuum toyield Compound 6 (39 mg; 11%).

R_(f) 0.1 (50% EtOAc/hexane/5% Et₃N); ¹H-NMR (CDCl₃) δ 1.5-1.74 (m, 3H),2.0-2.3 (m, 2H), 2.21 (m, 3H), 2.72 (ddd, 1H), 2.93 (m, 1H), 3.04 (s,3H), 3.13 (m, 1H), 3.38 (m, 1H), 3.5 (m, 1H), 3.62 (s, 3H), 7.13 (dd,1H), 7.30 (d, 1H), 7.31 (d, 1H).

EXAMPLE 9 2β-(1-Propanoyl)-3β-(4-fluorophenyl)tropane (Compound 7(R=4-F), FIG. 3)

A solution of2β-(N-methoxy-N-methylcarbamoyl)-3β-(4-fluorophenyl)-tropane, 6 (823 mg,2.7 mmol) in THF (10 mL) was cooled to 0° C. and EtMgBr/Et₂O (3M; 3 mL)was added dropwise over 4 min. The reaction was warmed to roomtemperature for 30 min and then heated to 65° C. for 45 min. The mixturewas cooled to 0° C. and quenched by addition of ethereal HCl (3M). Theresulting cloudy solution was basified with 2M Na₂CO₃. Ether (5 mL) wasadded and the layers separated and the aqueous layer washed with Et₂O(1×10 mL) and CHCl₃ (2×10 mL). The combined organic extracts were driedover Na₂SO₄, filtered and concentrated. The product was purified byflash column chromatography (eluent 25% EtOAc/hexanes/5% TEA) to provide7 (485 mg, 65%).

R_(f) 0.3 (20% EtOAc/hexanes/5% Et₃N); mp 118-119.5° C.; Elementalanalysis: calculated C, 74.15; H, 8.05; N, 5.09; found C, 74.05; H,8.09; N, 5.00. IR (KBr) 2900, 1710, 1500. 1250 cm⁻¹; ¹H-NMR (CDCl₃) δ0.85 (t, 3H), 1.5-1.8 (m, 4H), 2.0-2.4 (m, 3H), 2.23 (m, 3H), 2.5-2.6(m, 1H), 2.9-3.0 (m, 2H), 3.36 (m, 1H), 3.48 (m, 1H), 6.69 (m, 2H), 7.17(m, 2H).

EXAMPLE 10 2β-(1-Propanoyl)-3β-(3,4-dichlorophenyl)tropane (Compound 7(R=3,4-Cl₂), FIG. 3)

A solution of 2β-methoxymethylcarbamoyl-3β-(3,4-dichlorophenyl), 6 (168mg, 0.47 mmol) in THF (30 mL) was cooled to 0° C. and EtMgBr/Et₂O (3M; 1mL) was added dropwise over 3 min. The reaction was warmed to roomtemperature for 60 min and then heated to reflux for 10 min. The mixturewas cooled to room temperature and quenched by addition to ethereal HCl(3M, 20 mL). The resulting cloudy solution was basified with saturatedaqueous NaHCO₃ and brought to pH=10 by addition of Na₂CO₃. Ether wasadded and the layers separated and the aqueous layer washed with Et₂O(3×25 mL). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated. The product (166 mg) was purified by flashcolumn chromatography (eluent 30% EtOAc/hexanes/5% Et₃N) to provide 7(108 mg, 71%).

R_(f) 0.32 (50% EtOAc/hexanes/5% Et₃N); ¹H-NMR (CDCl₃) δ 0.9 (t, 3H),1.5-1.8 (m, 4H), 2.0-2.3 (m, 3H), 2.2 (m, 3H), 2.35-2.55 (m, 2H),2.82-2.92 (m, 1H), 2.96 (m, 1H), 3.34 (m, 1H), 3.54 (m, 1H), 7.75 (dd,1H), 7.27 (d, 1H), 7.29 (d, 1H).

EXAMPLE 11 2β-(1-Propanoyl)-3β-(4-fluorophenyl)nortropane (Compound 8(R=4-F), FIG. 3)

2β-(1-Propanoyl)-3β-(4-fluorophenyl)tropane, 7 (335 mg) was combinedwith 1-chloroethyl chloroformate (5 mL) and the solution was heated toreflux for 5 h. The excess chloroformate was removed in vacuo and theresidue was refluxed in methanol for 1.5 h. The methanol was removed invacuo and the residue was dissolved in CHCl₃ (15 mL) and shaken with 2MNa₂CO₃. The aqueous layer was extracted CHCl₃ (2×15 mL) and the combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated to yield369 mg. This residue was chromatographed (eluent: 100 mL EtOAc, 150 mL5% Et₃N/EtOAc, 100 mL 10% Et₃N/EtOAc, 300 mL 20% Et₃N/EtOAc, and 300 mL30% Et₃N/EtOAc). Like fractions were combined to yield 8 (104 mg, 33%).

R_(f) 0.36 (10% Et₃N/EtOAc); ¹H-NMR (CDCl₃) δ 0.70 (t, 3H), 1.4-1.8 (m,5H), 1.9-2.3 (m, 3H), 2.4 (m, 1H), 2.88(m, 1H), 3.18 (m, 1H), 3.56 (m,1H), 3.70 (m, 1H), 6.94 (m, 2H), 7.10 (m, 2H).

EXAMPLE 12 2β-(1-Propanoyl)-3β-(3,4-dichlorophenyl)nortropane (Compound8 (R=3,4-Cl₂), FIG. 3)

2β-(1-Propanoyl)-3β-(3,4-dichlorophenyl)tropane 7 (107 mg, 0.32 mmol)was combined with 1-chloroethyl chloroformate (2 mL) and the solutionwas heated to reflux for 5 h. The excess chloroformate was removed invacuo and the residue was refluxed in methanol for 45 min. The methanolwas removed in vacuo and the residue was dissolved in CH₂Cl₂ and shakenwith NaHCO₃/Na₂CO₃ (pH=9). The aqueous layer was extracted CH₂Cl₂ (4×10mL) and the combined organic extracts were dried (Na₂SO₄), filtered andconcentrated to yield 127 mg. This residue was chromatographed (1×100 mL5% Et₃N/EtOAc; 3×100 mL 10% Et₃N/EtOAc). Like fractions were combined toyield 8 (30 mg, 29%).

¹H-NMR (CDCl₃) δ 0.76 (t, 3H), 1.4-2.5 (m, 9H), 2.92 (m, 1H), 3.09-3.2(m, 1H), 3.6 (m, 1H), 3.72 (m, 1H), 7.0 (m, 1H), 7.25 (d, 1H), 7.32 (d,1H).

EXAMPLE 13N-[2-(3′-N′-Propyl-(1″R)-3″β-(4-fluorophenyl)tropane-2″β-(1-propanoyl))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol (Compound 9(R=4-F), FIG. 3 (O-1507)

2β-(1-Propanoyl)-3β-(4-fluorophenyl)nortropane 8 (27 mg) was combinedwith MAMA′-Cl (86 mg), KI (34 mg, 2.0 eq.), and NaHCO₃ (43 mg, 5 eq.) inanhydrous MeCN (4 mL) and brought to reflux for 4 h. The solvent wasremoved under vacuum and the residue was partitioned between CHCl₃ andsaturated aqueous NaHCO₃. The aqueous layer was extracted CHCl₃ (2×5 mL)and the combined organic extracts were dried (Na₂SO₄), filtered andconcentrated to yield a brown foam. The foam was applied to achromatography column (10 g silica; 40% EtOAc in hexanes/1% TEA).Fractions containing the product were combined and concentrated to yield9 as a light foam (47 mg, 46%).

R_(f) 0.09 (60% EtOAc/hexanes, 1% Et₃N). Elemental analysis: calculatedC, 72.15; H, 6.34; N, 3.96; found C, 71.99; H, 6.41; N, 3.92. ¹H-NMR(CDCl₃) δ 0.77 (t, 3H), 1.2-3.1 (m, 29H), 3.3-3.5 (m, 2H), 6.9-7.0 (m,2H), 7.1-7.6 (m, 32 H).

EXAMPLE 14N-[2-(3′-N′-Propyl-(1″R)-3″β-(3,4-dichlorophenyl)tropane-2″β-(1-propanoyl))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol (Compound 9(R=3,4-Cl₂), FIG. 3

2β-(1-Propanoyl)-3β-(3,4-dichlorophenyl)nortropane 8 (30 mg, 0.096 mmol)was combined with MAMA′-Cl (87 mg, 0.115 mmol, 1.2 eq.), KI (32 mg, 0.19mmol, 2.0 eq.), and NaHCO₃ (40 mg, 0.48 mmol, 5 eq.) in anhydrous MeCN(4 mL) and brought to reflux for 4 h then cooled to room temperature andallowed to stir overnight. The solvent was removed under vacuum and theresidue was partitioned between CH₂Cl₂ (15 mL) and saturated aqueousNaHCO₃ (15 mL). The aqueous layer was extracted with CH₂Cl₂ (3×10 mL)and the combined organic extracts were dried (Na₂SO₄), filtered andconcentrated to yield a yellow oil (115 mg). The oil was applied to achromatography column (10 g SiO₂; 30% EtOAc in hexanes/1% Et₃N).Fractions containing the product were combined and concentrated to yield9 as a light foam (41 mg, 41%).

R_(f) 0.14 (60% EtOAc/hexanes, 1% Et₃N). ¹H-NMR (CDCl₃) δ 0.81 (t, 3H),1.2-3.1 (m, 29H), 3.34 (m, 1H), 3.52 (m, 1H), 7.0-7.6 (m, 33H).

EXAMPLE 15N-[(2-((3′-N′-Propyl-(1″R)-3″β-(4-fluorophenyl)tropane-2″β-1-propanoyl)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]rhenium(V) oxide (Compound 10 (R=4-F), FIG. 3 (O-1508R)

N-[2-(3′-N′-Propyl-(1″R)-3″β-(4-fluorophenyl)tropane-2″β-(1-propanoyl))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol (22 mg, 0.023mmol) was dissolved in boiling EtOH (abs. 4 mL) and SnCl₂ (8.5 mg, in0.5 mL of 0.05M HCl). The reaction was maintained at reflux for afurther 6 h and silica was added and the solvents removed byevaporation. The silica adsorbed product was applied to a silica column(3 g eluent: 30% EtOAc in hexanes with 5% Et₃N). The compound wasobtained as a foam (6.7 mg, 44%).

R_(f) 0.07 (60% EtOAc in hexanes+NH₄OH (0.5%)) Accurate Mass calc forC₂₅H₃₅FN₃O₃ReS₂: 695.172; found 695.162. ¹H-NMR (CDCl₃) δ 0.7-0.9 (2t,2H), 1.4-4.1 (m, 26H), 4.5-4.6 (m, 1H), 4.73 (d, J=16.5 Hz, 0.5H) 4.87(d, J=16.5 Hz, 0.5H), 6.93 (m, 2H), 7.14 (m, 2H).

EXAMPLE 16 2β-(Carboxylic acid)-3α-(4-fluorophenyl)tropane (Compound 13(R=4-F), FIG. 4)

A solution of 2β-methoxycarbonyl-3α-(4-fluorophenyl)-tropane 12 (1.0 g,3.6 mmol) was refluxed for 24 h in 80 mL dioxane water (1:1). Thesolvent was removed in vacuo and the brown solid was purified by columnchromatography (eluent 30% MeOH/CHCl₃). The product (890 mg, 94%) wasobtained as a white foam.

R_(f) 0.43 (30% MeOH/CHCl₃); NMR ¹H-NMR (CDCl₃) δ 1.48-1.62 (m, 1H),1.75-2.1 (m, 3H), 2.36-2.46 (m, 1H), 2.60 (s, 3H), 2.7-2.82 (m, 1H),3.22 (brs, 1H), 3.5-3.62 (m, 2H), 3.76-3.84 (m, 1H), 6.9-7.1 (m, 2H),7.4-7.5 (m, 2H).

EXAMPLE 17 2β-(Carboxylic acid) 3α-(3,4-dichlorophenyl)tropane (Compound13 (R=3,4-Cl₂), FIG. 4)

A solution of 2β-methoxycarbonyl-3α-(3,4-dichlorophenyl)tropane 12 (750mg, 2.29 mmol) and LiOH (335 mg, 8.0 mmol) was brought to reflux for 4 hin water (10 mL) and THF:MeOH (33 mL; 1:1). The reaction was neutralizedby dropwise addition of conc. HCl. The solvent was removed in vacuo andthe product purified by column chromatography-(eluent 15% MeOH/CHCl₃).The product 13 (521 mg, 72%) was obtained as a solid.

R_(f) 0.15 (30% MeOH/CHCl₃); ¹H-NMR (CD₃OD) δ 1.59 (m, 1H), 1.8-1.9 (m,1H), 2.1-2.2 (m, 2H), 2.6-2.7 (m, 2H), 2.76 (s, 3H), 3.25 (brs, 1H),3.35 (brs, 1H), 3.85 (m, 1H), 3.93 (m, 1H), 7.5 (d, 1H), 7.53 (dd, 1H),7.8 (d, 1H).

EXAMPLE 18 2β-Methoxymethylcarbamoyl-3α-(4-fluorophenyl)tropane(Compound 14 (R=4-F), FIG. 4) (O-1403)

To a stirred suspension of Compound 13 (930 mg, 3.6 mmol) in anhydrousCH₂Cl₂ (80 mL) containing DMF (50 μL) was added oxalyl chloride (1 mL,11.4 mmol) dropwise resulting in copious bubbling and dissolution of thesuspension. The reaction was allowed to stir for 45 min during whichtime the solution became yellow. It was then reduced in vacuo and pumpedat high vacuum overnight, care being taken to bleed nitrogen into theevacuated flask when transferring from the rotary to the pump.

To the acid chloride dissolved in CH₂Cl₂ (70 mL) was added (MeO)MeNH.HCl(382 mg, 3.9 mmol) followed immediately by pyridine (1 mL). The reactionwas allowed to stir for 1 h and then partitioned between CHCl₃ (20 mL)and 2M Na₂CO₃ (20 mL). The aqueous layer was extracted with CHCl₃ (2×10mL) and the combined organic extracts were dried over Na₂SO₄, filteredand reduced in vacuo to yield a yellow oil. The oil was dissolved intoluene and concentrated to yield a yellow solid (653 mg). The crudeproduct was dissolved in a minimum volume of CHCl_(3,) and applied to achromatography column (28 g SiO₂; eluent 25% hexanes in EtOAc, 5% Et₃N;followed by 25% MeOH in CHCl₃). Product containing fractions werecombined and concentrated to yield the amide (540 mg; 50%).

R_(f) 0.25 (25% hexanes/EtOAc, 5% Et₃N); mp. 139.8-141.7° C.; ¹H-NMR(CDCl₃) δ 1.24 (dd, 1H), 1.4-1.8 (m, 3H), 2.1-2.3 (m, 2H), 2.23 (s, 3H);2.4-2.6 (m, 1H), 2.7 (brd, 1H), 3.05 (s, 3H), 3.05-3.1 (m, 1H), 3.25-3.5(m, 2H), 3.41 (s, 3H), 6.86-6.96 (m, 2H), 7.13-7.22 (m, 2H); IR (KBr)2900, 1656, 1500 cm⁻¹. Elemental analysis: calculated C, 66.65; H, 7.57;N, 9.14; found C, 66.37; H, 7.59; N, 9.0.

EXAMPLE 19 2β-Methoxymethylcarbamoyl-3α-(3,4-dichlorophenyl)tropane(Compound 14 (R=3,4-Cl₂), FIG. 4)

To a stirred suspension of the acid 13 (210 mg, 0.67 mmol) in anhydrousCH₂Cl₂ (10 mL) containing DMF (30 μL) was added oxalyl chloride (0.3 mL,2.0 mmol) dropwise. The reaction was allowed to stir for 1 h and thenreduced in vacuo and pumped at high vacuum overnight, care being takento bleed nitrogen into the evacuated flask when transferring from therotary to the pump.

To the acid chloride in CH₂Cl₂ (10 mL) was added (MeO)MeNH. HCl (72 mg,0.74 mmol) followed immediately by pyridine (0.3 mL). The reaction wasallowed to stir for 1.5 h and was partitioned between CH₂Cl₂ (10 mL) and1M Na₂CO₃ solution (5 mL). The aqueous layer was extracted with CH₂Cl₂(10 mL) and the combined organic extracts were dried over Na₂SO₄,filtered and reduced in vacuo to yield a yellow solid. The solid waspurified by column chromatography (14 g SiO₂, eluent 25% hexanes/EtOAc,5% Et₃N). Product containing fractions were combined and concentrated toyield the amide (115 mg; 48%).

R_(f) 0.14 (40% hexanes/EtOAc, 5% Et₃N); ¹H-NMR (CDCl₃) δ 1.17 (ddd,1H), 1.48 (ddd, 1H), 1.63 (ddd, 1H), 2.1-2.34 (m, 2H), 2.21 (s, 3H),2.42-2.54 (m, 1H), 2.65 (brd, 1H), 3.06 (s, 3H), 3.08 (brs, 1H),3.22-3.32 (m, 1H), 3.34-3.46 (m, 1H), 3.48 (s, 3H), 7.05 (dd, 1H), 7.25(d, 1H), 7.27 (d, 1H).

EXAMPLE 20 2β-(1-Propanoyl)-3α-(4-fluorophenyl)-tropane (Compound 15(R=4-F), FIG. 4) (O-1369)

A 250 mL round bottom flask containing the2β-methoxymethylcarbamoyl-3α-(4-fluorophenyl)tropane 14 (471 mg) wasflushed with nitrogen and charged with anhydrous THF (70 mL). At roomtemperature, EtMgBr/Et₂O (3.0 mL; 3.0M) was added dropwise over 3 min.The reaction was stirred at room temperature for 30 min and was thenheated to 65° C. for 1 h at which point no starting material wasobserved by TLC (TLC sample was prepared by adding an aliquot of thereaction to ethereal HCl, and basifying with 2M Na₂CO₃; R_(f) (product)0.42; R_(f) (starting material) 0.13 (20% EtOAc/hexanes, 5% Et₃N). Thereaction was cooled in an ice bath and quenched by slow addition ofethereal HCl. The cloudy solution was basified with 2M Na₂CO₃ anddiluted with ether (25 mL). The layers were separated and the aqueouslayer was extracted with ether (1×10 mL) and CHCl₃ (2×20 mL). Thecombined organic extracts were dried (Na₂SO₄), filtered and reduced invacuo to yield the crude residue (484 mg). This residue was thenchromatographed (25 g SiO₂; eluent 25% EtOAc/hexanes, 5% Et₃N).Fractions containing the product were combined and concentrated to yield15 (300 mg, 70%);

Mp. 60.5-61.3° C.; R_(f) 0.49 (33% EtOAc/hexanes; 5% Et₃N); ¹H-NMR(CDCl₃) δ 0.86 (t, 3H), 1.27 (ddd, 1H), 1.4-1.6 (m, 2H), 2.0-2.5 (m,6H), 2.23 (s, 3H), 3.12 (brd, 1H), 3.2-3.3 (m, 2H), 6.85-7.0 (m, 2H),7.05-7.15 (m, 2H); IR (KBr) 2900, 1740, 1500 cm⁻¹; Elemental analysis:calculated C, 74.15; H, 8.05; N, 5.09; found C, 74.00; H, 8.13; N, 4.98

EXAMPLE 21 2β-(1-Propanoyl)-3α-(3,4-dichlorophenyl)tropane (Compound 15(R=3,4-Cl₂), FIG. 4)

2-Methoxymethylcarbamoyl-3α-(3,4-dichlorophenyl)tropane, 14 (105 mg,0.29 mmol) was flushed with nitrogen and charged with anhydrous THF (15mL). At room temperature, EtMgBr/Et₂O (0.8 mL; 3.0M) was added dropwiseover 3 min. The reaction was stirred at room temperature for 1 h and wasthen heated to 55° C. for 30 min at which point no starting material wasobserved by TLC. The reaction was cooled in an ice bath and quenched byslow addition of ethereal HCl. The cloudy solution was basified with 2MNa₂CO₃ and diluted with ether (15 mL) and water (15 mL). The layers wereseparated and the aqueous layer was extracted with CHCl₃ (2×15 mL). Thecombined organic extracts were dried (Na₂SO₄), filtered and reduced invacuo to yield a residue (95 mg) which was chromatographed (5 g SiO₂,eluent 25% EtOAc in hexanes, 5% Et₃N). Fractions containing the productwere combined and concentrated to yield 15 (80 mg, 80%).

R_(f) 0.28 (30% EtOAc/hexanes; 5% Et₃N); ¹H-NMR (CDCl₃) 0.93 (t, J=7.4Hz, 3H), 1.27 (ddd, 1H), 1.42-1.62 (m, 2H), 2.06-2.30 (m, 6H), 2.21 (s,3H), 3.32-2.52 (m, 3H), 3.14 (brd 1H), 3.2-3.36 (m, 2H), 7.10 (dd, 1H),7.24 (d, 1H), 7.29 (d, 1H).

EXAMPLE 21a 2β-(1-Propanoyl)-3α-(3,4-dichlorophenyl)tropane (Compound 15(R-3,4-Cl₂), FIG. 4)

To commercially available ethylmagnesium bromide (1M in THF, 12.6 mL,12.6 mmol) in a flask equipped with an addition funnel under nitrogenwas added triethylamine (5.0 g, 50.4 mmol). To the resulting mixture wasadded drop-wise a solution of compound 12 (R=Cl₂, 750 mg, 2.29 mmol) inbenzene (10 mL) at 5-10° C. over a period of 1 hour. The reactionmixture was then stirred at 5-10° C. for 5 hours and then treated with 4M HCl (2.9 mL, 11.6 mmol). The organic layer was washed with water (1×50mL), 5% NaHCO₃ (aq) (1×50 mL) and water (2×50 mL). The organic phase wasthen dried (K₂CO₃), filtered and the concentrated. The residue waschromatographed (SiO₂. 25% EtOAc in hexanes with 5% Et₃N) and gave 670mg (85%) of compound 15 with the same physical and spectralcharacteristics as previously reported (Example 21).

EXAMPLE 22 2β-(1-Propanoyl)-3α-(4-fluorophenyl)nortropane Compound 16(R=4-F), FIG. 4) (O-1370

2β-(1-Propanoyl)-3α-(4-fluorophenyl)tropane 15 (O-1369) (556 mg, 2 mmol)and ACE-Cl (7 mL) were combined and brought to reflux for 4 h. Allvolatiles were removed by evaporation and methanol (100 mL) was added tothe residue. The resulting mixture was brought to reflux for 90 min.Volatiles were removed and the residue was taken up in CHCl₃ and washedwith aq. 2M Na₂CO₃. The aqueous mixture was extracted with CHCl₃ (2×10mL) and organic fractions combined, dried (Na₂SO₄), filtered andreduced. The dark brown oil (615 mg) was chromatographed (SiO₂, 20 g;0-10% Et₃N in EtOAc) and gave 390 mg (74%) of a yellow oil.

R_(f) 0.25 (5% Et₃N in EtOAc); ¹H-NMR (CDCl₃) δ 0.86 (t, 3H), 1.27 (ddd,1H), 1.50-1.72 (m, 2H), 1.8-2.1 (m, 3H), 2.2-2.4 (m, 2H), 2.56 (dd,J=10.7, 1 Hz, 1H), 3.07 (ddd, J=11.3, 10.9, 7.1 Hz, 1H), 3.43 (brd 1H),3.62 (brt, 1H), 6.89-6.99 (m, 2H), 7.09-7.16 (m, 2H). IR (KBr) 2900,1711, 1500 cm⁻¹; Elemental analysis: calculated (0.2 H₂O) C, 72.52; H,7.77; N, 5.25; found C, 72.65; H, 7.81; N, 5.27

EXAMPLE 23 2β-(1-Propanoyl)-3α-(3,4-dichlorophenyl)nortropane (Compound16 (R=3,4-Cl₂), FIG. 4)

2β-(1-Propanoyl)-3-(3,4-dichlorophenyl)tropane, 15 (80 mg, 2.45 mmol)was combined with 1-chloroethyl chloroformate (3 mL) and the solutionwas heated to reflux for 5 h. The excess chloroformate was removed invacuo and the residue was refluxed in methanol for 1 h. The methanol wasremoved in vacuo and the residue was dissolved in CHCl₃ and washed with2M Na₂CO₃. The aqueous layer was extracted with CHCl₃ (2×5 mL) and thecombined organic extracts were dried (Na₂SO₄), filtered and concentratedto yield pure compound (77 mg; 100%).

R_(f) 0.3 (5% Et₃N/EtOAc); ¹H-NMR (CDCl₃) δ 0.91 (t, 3H), 1.25 (ddd, 1H,1.52-1.74 (m, 2H), 1.8-2.56 (m, 7H), 3.06-3.2 (m, 1H), 3.45 (d, 1H),3.62 (brt, 1H), 7.01 (dd, 1H), 7.25 (d, 1H), 7.31 (d, 1H).

EXAMPLE 24N-[2-(3′-N′-Propyl-(1″R)-3″α-(4-fluorophenyl)tropane-2″β-(1-propanoyl))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol (compound 17(R=4-F), FIG. 4) (O-1506

2β-(1-Propanoyl)-3α-(4-fluorophenyl)nortropane 16 (24 mg, 0.09 mmol),MAMA′-Cl (147 mg, 0.19 mmol), KI (31 mg, 19 mmol) were all dissolved inCH₃CN (3 mL) and brought to reflux for 3 h. Solvent was removed in vacuoand the residue partitioned between satd. aq NaHCO₃ and CHCl₃. Theaqueous layer was further extracted with CHCl₃, all organic fractionswere combined and dried (Na₂SO₄), filtered and concentrated. Columnchromatography (20% EtOAc, 79% Hexane, 1% Et₃N) gave pure product as agolden foam (11.5 mg, 13%).

R_(f) 0.15 (50% EtOAc in hexanes+5% Et₃N); Elemental analysis:calculated (0.1H₂O) C, 75.79; H, 6.87; N, 4.21; found C, 75.35; H, 6.81;N, 4.13. ¹H-NMR (CDCl₃) δ 0.85 (t,3H), 1.19 (ddd, 1H), 1.3-1.5 (m, 6H),1.8-2.6 (m, 14H), 2.85 (brs, 2H), 3.0 (m, 2H), 3.08-3.30 (m, 3H),6.88-6.96 (m, 2H), 7.06-7.42 (m, 32H).

EXAMPLE 25N-[2-(3′-N′-Propyl-(1″R)-3″α-(3,4-dichlorophenyl)tropane-2″β-(1″′-propanoyl))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol (Compound 17(R=3,4-Cl₂), FIG. 4) (O-1546)

2β-(1-Propanoyl)-3α-(3,4-dichlorophenyl)nortropane 16 (75 mg, 0.24 mmol)was combined with N-(((2-(2-(triphenylmethyl)thio)ethyl)(N′-3′-chloropropyl)amino)acetyl)-S-(triphenylmethyl)-2-aminoethanethiol(MAMA′-Cl) (218 mg, 0.29 mmol), KI (80 mg, 0.48 mmol), and NaHCO₃ (101mg, 1.2 mmol) in anhydrous MeCN (20 mL) and brought to reflux for 4 hthen cooled to room temperature. The solvent was removed under vacuumand the residue was partitioned between CH₂Cl₂ (20 mL) and saturatedaqueous NaHCO₃ (15 mL). The aqueous layer was extracted with CH₂Cl₂(1×10 mL) and the combined organic extracts were dried (Na₂SO₄),filtered and concentrated to yield a brown oil. The oil was applied to achromatography column (30 g SiO₂; eluent: 25% EtOAc/hexanes/1% Et₃N).Fractions containing the product were combined and concentrated to yield17 (51 mg, 17%).

R_(f) 0.3 (60% EtOAc in hexanes, 1% Et₃N); Elemental analysis:calculated (1.33 H₂O) C, 71.71; H, 6.46; N, 3.98; found C, 71.85; H,6.52; N, 3.91. ¹H-NMR (CDCl₃) δ 0.89 (t, 3H), 1.0-1.7 (m, 8H), 1.8-2.5(m, 14H), 2.6-3.4 (m, 6H), 6.9-7.6 (m, 33H).

EXAMPLE 26N-[(2-((3′-N′-Propyl-(1″R)-3″α-(4-fluorophenyl)tropane-2″β-1″′-propanoyl)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]rhenium (V) oxide(Compound 18 (R=4-F), FIG. 4) (O-1505)

A solution ofN-[2-(3′-N′-Propyl-(1″R)-3″α-(4-fluorophenyl)tropane-2″β-(1″′-propanoyl))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol, 17 (22 mg) inEtOH (4 mL) was heated to reflux. A solution of SnCl₂ (7.8 mg, 0.04mmol) in 0.005 M HCl (0.5 mL) was added quickly followed immediately byNaReO₄ (12.4 mg, 0.04 mmol) in 0.005 M HCl (0.5 mL). The cloudy solutionwas refluxed for 6 h and was then loaded onto 0.5 g silica and pumpedovernight. The silica-adsorbed material was applied to a chromatographycolumn (3 g SiO₂; eluent 30% EtOAc/hexanes/5% TEA). The purple brownsolid obtained was triturated with pentane and dried at high vacuumovernight to yield 18 as a foam (9.9 mg; 71%).

Accurate Mass calc 695.161 (found, 695.172). R_(f) 0.30 (75% EtOAc inhexane+0.5% NH₄OH); ¹H-NMR (CDCl₃) δ 0.75-0.95 (2t, 3H), 1.0-2.0 (m,8H), 2.0-2.5 (m, 6H), 2.8-3.0 (m, 1H), 3.0-3.5 (m, 7H), 3.6-3.8 (m, 1H),3.9-4.2 (m, 3H), 4.5-4.65 (m, 1H), 4.73, 5.12 (2d, J=16.7 Hz), 6.9-7.0(m, 2H), 7.08-7.15 (m, 2H).

EXAMPLE 27N-[(2-((3′-N′-Propyl-(1″R)-3″α-(3,4-dichlorophenyl)tropane-2″β-1″′-propanoyl)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]rhenium (V) oxide(Compound 18 (R=3,4-Cl₂), FIG. 4)

A solution ofN-[2-(3′-N′-Propyl-(1″R)-3″α-(3,4-dichlorophenyl)tropane-2″β-(1-propanoyl))(2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol, 17, (24 mg,0.024 mmol) in EtOH (5 mL) was heated to reflux. A solution of SnCl₂ (9mg, 0.05 mmol) in 0.005 M HCl (0.5 mL) was added quickly followedimmediately by NaReO₄ (14.5 mg, 0.05 mmol) in 0.005 M HCl (0.5 mL). Thesolution was refluxed for 4 h and was then loaded onto 0.5 g silica andpumped at high vacuum overnight. The silica-adsorbed material wasapplied to a chromatography column (4 g SiO₂; eluent 30%EtOAc/hexanes/5% Et₃N). The solid obtained was concentrated to yield 18(4.6 mg; 27%).

¹H-NMR (CDCl₃) δ 0.8-1.0 (2t, 3H), 1.1-2.5 (m, 14H), 2.8-3.0 (m, 1H),3.0-3.5 (m, 7H), 3.6-3.8 (m, 1H), 3.9-4.2 (m, 3H), 4.4-4.65 (m, 1H),4.70, 5.06 (2d, 2×J=16.7 Hz, 1H), 7.0 (dd, 1H), 7.3 (d, 1H), 7.34 (d,1H).

EXAMPLE 28 2β-(Methoxymethylcarbamoyl-3α-(4-fluorophenyl)nortropane(Compound 20 (R=4-F), FIG. 5)

2β-(1-Propanoyl)-3α-(4-fluorophenyl)tropane 14 (112 mg, 0.37 mmol) wascombined with 1-chloroethyl chloroformate (2.2 mL) and the solution washeated to reflux for 5 h. The excess chloroformate was removed in vacuoand the residue was refluxed in methanol for 45 min. The MeOH wasremoved in vacuo and the residue was dissolved in CHCl₃ andNaHCO₃/Na₂CO₃ (pH=9). The aqueous layer was extracted CHCl₃ (3×10 mL)and the combined organic extracts were dried (Na₂SO₄), filtered andconcentrated to yield 104 mg. This residue was chromatographed (eluent:10-20% Et₃N in EtOAc). Like fractions were combined to yield 20 (65 mg,60%).

R_(f) 0.13 (10% Et₃N in EtOAc); ¹H-NMR (CDCl₃) δ 1.30 (ddd, 1H),1.5-1.75 (m, 2H), 1.85-2.15 (m, 2H), 2.2-2.35 (m, 1H), 2.7-2.9 (m, 1H),3.05 (s, 3H), 3.1-3.22 (m, 1H), 3.38 (s, 3H), 3.4-3.5 (m, 1H), 3.6-3.7(m, 1H), 6.9-7.0 (m, 2H), 7.13-7.23 (m, 2H).

EXAMPLE 29N-[2-(3′-N′-Propyl-(1″R)-3″α-(4-fluorophenyl)tropane-2″β-(methoxymethylcarbamoyl))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol(Compound 21 (R=4-F), FIG. 5) (O-1450)

2β-(1-Propanoyl)-3α-(4-fluorophenyl)nortropane 20 (65 mg, 0.22 mmol) wascombined with MAMA′-Cl (203 mg, 0.27 mmol, 1.2 eq.), KI (74 mg, 0.45mmol), and K₂CO₃ (309 mg, 2.2 mmol) in anhydrous MeCN (10 mL) andbrought to reflux for 6 h then cooled to room temperature. The solventwas removed under vacuum and the residue was partitioned between CHCl₃and water. The aqueous layer was extracted with CHCl₃ (3×5 mL) and thecombined organic extracts were dried (Na₂SO₄), filtered and concentratedto yield a yellow oil which was applied to a chromatography column (15 gSiO₂ eluent 120 mL of 50% EtOAc/hexanes/5% Et₃N). Fractions containingthe product were combined and concentrated to yield 21 as a light yellowoil (142 mg, 41%).

R_(f) 0.7 (5% Et₃N/EtOAc); Elemental analysis: calculated (0.3H₂O) C,71.02; H, 6.96; N, 5.26; found C, 71.20; H, 6.45; N, 5.14. ¹H-NMR(CDCl₃) δ 1.2-3.5 (m, 24H), 2.85 (s, 2H), 3.02 (s, 3H), 3.42 (s, 3H),6.85-7.0 (m, 2H), 7.1-7.7 (m, 32H).

EXAMPLE 30 N-[(2-((3′-N′-Propyl-(1″R)-3″α-(4-fluorophenyl)tropane-2″β-methoxymethylcarbamoyl)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]rhenium (V) oxide(Compound 22 (Re: R=4-F), FIG. 5) (O-1451)

N-[2-(3′-N′-propyl-(1″R)-3″α-(4-fluorophenyl)tropane-2″β-(methoxymethylcarbamoyl))(2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol21 (21 mg, 0.02 mmol) in EtOH (4 mL) was heated to reflux. A solution ofSnCl₂ (8.4 mg, 0.04 mmol) in 0.005 M HCl (0.5 mL) was added quicklyfollowed immediately by NaReO₄ (13 mg, 0.04 mmol) in 0.005 M HCl (0.5mL). The solution was refluxed for 10 h and was then loaded onto 0.5 gsilica and pumped overnight. The silica-adsorbed material was applied toa chromatography column (3 g SiO₂, eluent 30% EtOAc/hexanes/5% Et₃N).Like fractions were combined and concentrated to yield as a purple foam(3.7 mg; 26%).

R_(f) 0.5 (25% hexanes in EtOAc); ¹H-NMR (CDCl₃) δ 1.1-4.2 (m, 30H),4.5-4.6 (m, 1H), 4.75, 5.12 (2d, J=16.7 Hz, 2×6β, 1H), 6.8-7.0 (m, 2H),7.1-7.2 (m, 2H).

EXAMPLE 31 2β-Methoxymethylcarbamoyl-3β-(4-fluorophenyl)nortropane(Compound 20A (R=4-F), FIG. 5)

2β-(1-Propanoyl)-3β-(4-fluorophenyl)tropane (143 mg, 0.50 mmol) wascombined with 1-chloroethyl chloroformate (2 mL) and the solution washeated to reflux for 2 h. The excess chloroformate was removed in vacuoand the residue was refluxed in methanol (30 mL) for 45 min. Themethanol was removed in vacuo and the residue was dissolved in CHCl₃ andNaHCO₃/Na₂CO₃ (pH=9). The aqueous layer was extracted CHCl₃ (3×10 mL)and the combined organic extracts were dried (Na₂SO₄), filtered andconcentrated. The residue was chromatographed (10-20% Et₃N in EtOAc).Like fractions were combined to yield 80 mg (58%).

¹H-NMR (CDCl₃) δ 1.50 (m, 1H), 1.7 (m, 2H), 1.95-2.22 (m, 2H), 2.5 (ddd,1H), 2.92 (s, 3H), 3.1-3.4 (m, 2H), 3.3 (s, 3H), 3.6 (m, 1H), 3.72 (m,1H), 6.9-7.0 (m, 2H), 7.1-7.3 (m, 2H).

EXAMPLE 32N-[2-(3′-N′-Propyl-(1″R)-3″β-(4-fluorophenyl)tropane-2″β-methoxymethylcarbamoyl)((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol(Compound 21A (R=4-F), FIG. 5)

2β-(1-Propanoyl)-3β-(4-fluorophenyl)nortropane (80 mg, 0.28 mmol) wascombined with MAMA′-Cl (244 mg, 0.32 mmol,), KI (84 mg, 0.5 mmol, 2.0eq.), and K₂CO₃ (322 mg, 2.3 mmol) in anhydrous MeCN (10 mL) and broughtto reflux overnight then cooled to room temperature. The solvent wasremoved under vacuum and the residue was applied to a chromatographycolumn (5% Et₃N in EtOAc). Fractions containing the product werecombined and concentrated to yield the product as a light yellow foam(80 mg, 29%).

R_(f) 0.65 (5% Et₃N in EtOAc); ¹H-NMR (CDCl₃) δ 1.2-3.1 (m, 28H), 3.37(m, 1H), 3.51 (s, 3H), 3.55 (m, 1H), 6.9-7.0 (m, 2H), 7.1-7.5 (m, 32H).

EXAMPLE 33N-((2-((3′-N′-Propyl-(1″R)-3″β-(4-fluorophenyl)tropane-2″β-methoxymethylcarbamoyl)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]rhenium (V) oxide(Compound 22A (Re: R=4-F), FIG. 5) (O-1451)

N-[2-(3′-N′-propyl-(1″R)-3″β-(4-fluorophenyl)tropane-2″β-methoxymethylcarbamoyl)((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol(22 mg, 0.02 mmol) in EtOH (10 mL) was heated to reflux. A solution ofSnCl₂ (8.4 mg, 0.05 mmol) in 0.005 M HCl (1.0 mL) was added quicklyfollowed immediately by NaReO₄ (13 mg, 0.05 mmol) in 0.005 M HCl (0.5mL). The solution was refluxed for 10 h and was then applied to achromatography column (65% EtOAc/hexanes/5% Et₃N). Like fractions werecombined and concentrated to yield a foam (10 mg; 65%).

R_(f) 0.44 (5% Et₃N, 30% hexanes in EtOAc); ¹H-NMR (CDCl₃) δ 1.5-4.2 (m,30H), 4.4-4.6 (m, 1H), 4.72, 5.05 (2d, J=16.5 Hz, 1H), 6.8-7.0 (m, 2H),7.1-7.3 (m, 2H).

EXAMPLE 34 (1R)-N-Methyl-2-hydroxymethyl-3-(4-fluorophenyl)-8-aza-bicyclo[3.2.1]oct-2-ene(Compound 38 (R=4-F), FIG. 9) (O-1337)

(1R)-N-Methyl-2-methoxycarbonyl-3-(4-fluorophenyl)-8-azabicyclo[3.2.1]oct-2-ene 3 (500 mg, 1.82 mmol) was dissolved in benzene (15 mL)and LAH (70 mg, 1.82 mmol) was added. The reaction was heated to 60° C.overnight. The reaction was cooled to 0° C., and water (70 μL), 15% NaOH(70 μL), water (200 μL) were added. The reaction was stirred for 15 minand then the salts were filtered off through a pad of celite. Thefiltrate was dried over Na₂SO₄ filtered and concentrated to yield 38(454 mg, 90%) which was purified by column chromatography (30 g SiO₂;eluent: 4% Et₃N in 10% MeOH/CHCl₃). Like fractions were combined,reduced and pumped at high vacuum overnight to yield 38 (336 mg, 74%).

Mp. 106.6-108.7° C.; R_(f) 0.2 (10% MeOH/CHCl₃; 5% Et₃N); ¹H-NMR (CDCl₃)δ 1.5-1.7 (m, 1H), 1.9-2.0 (m, 3H), 2.1-2.3 (m, 2H), 2.4 (s, 3H), 2.72(brd, J=18 Hz, 1H), 3.31 (br s, 1H), 3.55 (d, J=4.1 Hz, 1H), 3.89 (d,J=12.3 Hz, 1H), 4.02 (d, J=12.3 Hz, 1H), 6.9-7.0 (m, 2H), 7.1-7.2 (m,2H). Elemental analysis: calculated C, 72.85; H, 7.34; N, 5.66; found C,72.94; H, 7.33; N, 5.73.

EXAMPLE 35(1R)-N-Methyl-2-hydroxymethyl-3-(3,4-dichlorophenyl)-8-aza-bicyclo[3.2.1]oct-2-ene(Compound 38 (R=3,4-Cl₂), FIG. 9)

(1R)-N-Methyl-2-methoxycarbonyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]-oct-2-ene3 (508 mg, 1.56 mmol) was dissolved in benzene (20 mL) and LAH (62 mg,1.56 mmol) was added. The reaction was heated to reflux overnight. Thereaction was cooled to 0° C., and water (80 μL), 10% KOH (90 μL), water(300 μL) were added.

The reaction was stirred for 15 min and then the salts were filtered offthrough a pad of celite. The filtrate was dried over Na₂SO₄ filtered andconcentrated to yield a yellow foam (420 mg, 90%) and purified by columnchromatography (3% Et₃N/7% MeOH in CHCl₃) to give 280 mg (60%).

R_(f) 0.2 (5% MeOH/CHCl₃; 3% Et₃N); ¹H-NMR (CDCl₃) δ 1.5-1.66 (m, 1H),1.84-1.98 (m, 2H), 2.0 (m, 2H), 2.08-2.24 (m, 2H), 2.39 (s, 3H), 2.7(dd, 1H), 3.3 (m, 1H), 3.54 (d, J=5.5 Hz, 1H), 3.89 (d, J=11.8 Hz, 1H),4.01 (d, J=11.8 Hz, 1H), 6.99 (dd, 1H), 7.25 (d, 1H), 7.37 (d, 1H).

EXAMPLE 36(1R)-N-Methyl-2-carbonyl-3-(4-fluorophenyl)-8-azabicyclo[3.2.1]-oct-2-ene(Compound 39 (R=4-F), FIG. 9)

A solution of (COCl)₂ (55 mg, 40 μL, 0.43 mmol) and CH₂Cl₂ (2 mL) wascooled to −78° C. and DMSO (65 μL) was added dropwise over 3 min. Thereaction was stirred for a further 5 min at −78° C. and compound 38 (90mg, 0.36 mmol) in CH₂Cl₂ (2 mL) was added dropwise over 10 min. After afurther 20 min, Et₃N (250 μL, 1.80 mmol) was added over 30 min. Thereaction was stirred for a further 10 min and then allowed to warm toroom temperature. CH₂Cl₂ (20 mL) and 1M NaOH was added, the layerspartitioned and the aqueous layer was washed with CH₂Cl₂ (1×15 mL).Combined organic extracts were dried over Na₂SO₄, filtered, concentratedand pumped at high vacuum. The yellow oil obtained (86 mg) was purifiedby column chromatography (4.5g SiO₂; 30% EtOAc/hexanes/5% Et₃N) and likefractions were combined, concentrated and dried at high vacuum to yieldthe product 39 (62 mg, 63%).

R_(f) 0.2 (20% EtOAc/hexane, 5% Et₃N); ¹H-NMR (CDCl₃) δ 1.55-1.65 (m,1H), 1.72-1.82 (m, 2H), 2.14-2.3 (m, 2H), 2.40 (s, 3H), 2.9-3.0 (m, 1H),3.36-3.44 (m, 1H), 4.02-4.30 (m, 1H),7.0-7.1 (m, 2H), 7.16-7.24 (m, 2H),9.45 (s, 1H).

EXAMPLE 37(1R)-N-Methyl-2-carbonyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene(Compound 39 (R=3,4-Cl₂), FIG. 9)

A solution of (COCl)₂ (125 mg, 87 μL, 1.0 mmol) and CH₂Cl₂ (20 mL) wascooled to −78° C. and DMSO (150 μL) was added dropwise over 3 min. Thereaction was stirred for a further 5 min at −78° C. and compound 38 (245mg, 0.82 mmol) in CH₂Cl₂ (5 mL) was added dropwise over 7 min. After afurther 30 min, Et₃N (600 μL, 4.0 mmol) was added over about 15 min. Thereaction was stirred for a further 10 min. and then allowed to warm toroom temperature. CH₂Cl₂ (20 mL) and Na₂CO₃ (20 mL; 1M) was added, thelayers partitioned and the aqueous layer was washed with CH₂Cl₂ (1×20mL). Combined organic extracts were dried Na₂SO₄, filtered, concentratedand pumped at high vacuum. The residue was purified by columnchromatography (25g SiO₂; 60% EtOAc/hexanes/5% Et₃N) and like fractionswere combined, concentrated and dried at high vacuum to yield theproduct 39 (154 mg, 63%).

R_(f) 0.2 (75% EtOAc/hexane, 5% Et₃N); ¹H-NMR (CDCl₃) δ 1.5-1.7 (m, 1H),1.7-1.85 (m, 1H), 2.1-2.3 (m, 2H), 2.38 (s, 3H), 2.93 (dd, 1H), 3.39 (m,1H), 4.05 (dd, 1H),7.08 (dd, 1H), 7.34 (d, 1H), 7.46 (d, 1H), 9.45 (s,1H).

EXAMPLE 38(1R)-N-Methyl-2-(2-hyroxypropyl)-3-(4-fluorophenyl)-8-azabicyclo[3.2.1]oct-2-ene(Compound 40 (R=4-F), FIG. 9)

Compound 39 (62 mg, 0.26 mmol) was dissolved in anhydrous THF at roomtemperature and EtMgBr/Et₂O (3M; 900 μl) was added dropwise. Thereaction was stirred at room temperature for 20 min and then at 65° C.overnight, and then added slowly to a mixture of 1M HCl (50 mL) and Et₂O(50 mL) at 0° C. The mixture was basified with saturated aq. Na₂CO₃ andseparated. The aqueous layer was extracted with CHCl₃ (2×20 mL), dried(Na₂SO₄), filtered, evaporated and dried at high vacuum. The residue (90mg) was purified by column chromatography (6 g SiO₂; 5% Et₃N/EtOAc) andlike fractions were combined, evaporated and dried at high vacuum toyield 40 (82 mg, 52%).

R_(f) 0.4 (10% MeOH/CHCl₃/5% Et₃N); ¹H-NMR (CDCl₃) δ 0.83 (t, J=7.6 Hz,3H), 1.4-1.7 (m, 4H), 1.81 (d, J=18 Hz, 1H), 2.0 (m, 1H), 2.1-2.3 (m,2H), 2.42 (s, 3H), 2.7 (m, 1H), 3.3 (m, 1H), 3.53 (m, 1H), 4.1-4.2 (m,1H), 6.9-7.1 (m, 4H)

EXAMPLE 39(1R)-N-Methyl-2-(2-hyroxypropyl)-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene(Compound 40 (R=3,4-Cl₂), FIG. 9)

Compound 39 (150 mg, 0.5 mmol) was dissolved in anhydrous THF (25 mL) atroom temperature and EtMgBr/Et₂O (3M; 350 μl, 1.05 mmol) was addeddropwise over 2 min. The reaction was stirred at room temperature for2.75 h and then added slowly to a mixture of 1M HCl (20 mL) and Et₂O (20mL). The mixture was basified with saturated aq. Na₂CO₃ and separated.The aqueous layer was extracted with CHCl₃ (3×20 mL) dried (Na₂SO₄),filtered, evaporated and dried at high vacuum. The residue (197 mg) waspurified by column chromatography (20 g SiO₂; 5% Et₃N/EtOAc) and likefractions were combined, evaporated and dried at high vacuum to yield 40(109 mg, 66%).

R_(f) 0.07 (5% Et₃N, 20% hexane in EtOAc); ¹H-NMR (CDCl₃) δ 0.85 (t,J=7.4 Hz, 3H), 1.4-1.7 (m, 4H), 1.79 (d, J=17.6 Hz, 1H), 1.95-2.1 (m,1H), 2.1-2.3 (m, 2H), 2.42 (s, 3H), 2.68 (dd, J=4, 18 Hz, 1H), 3.3 (m,1H), 3.38 (d, 1H), 3.52 (d, J=5 Hz, 1H), 4.1-4.2 (m, 1H), 6.94 (dd, 1H),7.20 (dd, 1H).

EXAMPLE 40(1R)-2-Propanoyl-3-(4-fluorophenyl)-8-azabicyclo[3.2.1]-oct-2-ene(Compound 26 (R=4-F), FIG. 9)

Tropane 40 (28 mg, 0.1 mmol) in CH₂Cl₂ was added dropwise to a cold(−78° C.) solution of (COCl)₂ (5.5 μL, 0.12 mmol) and DMSO (20 μL, 0.26mmol) in CH₂Cl₂. After stirring for 30 min at −78° C., Et₃N (75 μL, 0.5mmol) was added and the reaction was warmed to room temperature. CH₂Cl₂and 1M NaOH were added and the layers separated. The organic layer wasdried (Na₂SO₄), filtered and evaporated and the product applied to achromatography column (5% Et₃N, 25% hexane, 70% EtOAc) to give 18.6 mgof product (66%).

R_(f) 0.2 (5% Et₃N, 25% Hexanes, 70% EtOAc); ¹H-NMR (CDCl₃) δ 0.80 (t,3H), 1.6 (m, 1H), 1.8-2.3 (m, 6H), 2.40 (s, 3H), 2.75 (dd, 1H), 3.35 (m,1H), 3.73 (m, 1H), 7.0 (m, 2H), 7.05-7.15 (m, 2H).

EXAMPLE 41(1R)-2-Methoxycarbonyl-3-(4-fluorophenyl)-8-norazabicyclo[3.2.1]-oct-2-ene(Compound 29 (R=4-F), FIG. 7) (O-1131)

2-Methoxycarbonyl-3-(4-fluorophenyl)tropene 3 (362 mg, 1.3 mmol) wascombined with 1-chloroethyl chloroformate (1 mL) and the solution washeated to reflux for 2 h. The excess chloroformate was removed in vacuoand the residue was refluxed in methanol (30 mL) for 45 min. Themethanol was removed in vacuo and the residue was dissolved in CHCl andNaHCO₃/Na₂CO₃ (pH=9). The aqueous layer was extracted CHCl (3×10 mL) andthe combined organic extracts were dried (Na₂SO₄), filtered andconcentrated. The residue was chromatographed (eluent: 1-3% Et₃N inEtOAc+0.5% NH₄OH). Like fractions were combined to yield a yellow solid(234 mg, 68%).

R_(f) 0.7 (10% MeOH in hexanes+0.5% NH₄OH); mp. 67-68° C.; ¹H-NMR(CDCl₃) δ 1.50-3.0 (m, 6H), 3.8 (m, 1H), 4.2 (m, 1H), 6.8-7.2 (m, 4H).Elemental analysis: calculated C, 68.95; H, 6.17; N, 5.36; found C,68.81; H, 6.24; N, 5.40.

EXAMPLE 42(1R)-2-Methoxycarbonyl-3-(3,4-dichlorophenyl)-8-norazabicyclo[3.2.1]oct-2-ene(Compound 29 (R=3,4-Cl₂), FIG. 7) (O-1130)

2-Methoxycarbonyl-3-(3,4-dichlorophenyl)tropene (200 mg, 0.61 mmol) wascombined with 1-chloroethyl chloroformate (4 mL) and the solution washeated to reflux for 2 h. The excess chloroformate was removed in vacuoand the residue was refluxed in methanol (30 mL) for 45 min. Themethanol was removed in vacuo and the residue was dissolved in CHCl₃ andNaHCO₃/Na₂CO₃ (pH=9). The aqueous layer was extracted CHCl₃ (3×10 mL)and the combined organic extracts were dried (Na₂SO₄), filtered andconcentrated. The residue was chromatographed (eluent: 5-15% Et₃N inEtOAc). Like fractions were combined to yield a yellow oil.

R_(f) 0.3 (10% Et₃N in EtOAc); ¹H-NMR (CDCl₃) δ 1.50-2.3 (m, 5H),2.5-2.9 (m, 1H), 3.53 (s, 3H), 3.8 (m, 1H), 4.2 (m, 1H), 6.9 (dd, 1H),7.2 (dd, 1H), 7.4 (d, 1H). Elemental analysis: calculated C, 57.71; H,4.84; N, 4.49; found C, 57.45; H, 4.87; N, 4.47.

EXAMPLE 43N-[2-(3′-N′-Propyl-(1″R)-3″-(4-fluorophenyl)trop-2-ene-2″-(methoxycarbonyl))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol(Compound 30 (R=4-F), FIG. 7)

2-(1-Methoxycarbonyl)-3-(4-fluorophenyl)nortrop-2-ene (134 mg, 0.5 mmol)was combined with MAMA′-Cl (387 mg, 0.5 mmol,), KI (85 mg, 0.5 mmol),and K₂CO₃ (707 mg, 5 mmol) in anhydrous MeCN (10 mL) and brought toreflux overnight then cooled to room temperature. The solvent wasremoved under vacuum and the residue was applied to a chromatographycolumn (1-6% Et₃N in EtOAc). Fractions containing the product werecombined and concentrated to yield the product as a light yellow foam(148 mg, 29%).

R_(f) 0.18 (10% Et₃N in hexane); ¹H-NMR (CDCl₃) δ 1.3-3.15 (m, 22H),3.2-3.4 (m, 1H), 3.5 (s, 3H), 3.8-3.9 (m, 1H), 6.8-7.8 (m, 34H).

EXAMPLE 44N-[2-(3′-N′-Propyl-(1″R)-3″-(3,4-dichlorophenyl)trop-2-ene-2″-(methoxycarbonyl)((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol (Compound 30(R=3,4-Cl₂), FIG. 7)

2-(1-Methoxycarbonyl)-3-(3,4-dichlorophenyl)nortrop-2-ene (107 mg, 0.34mmol) was combined with MAMA′-Cl (258 mg, 0.34 mmol,), KI (57 mg, 0.34mmol), and K₂CO₃ (472 mg, 3.4 mmol) in anhydrous MeCN (10 mL) andbrought to reflux overnight then cooled to room temperature. The solventwas removed under vacuum and the residue was applied to a chromatographycolumn (1-6% Et₃N in EtOAc). Fractions containing the product werecombined and concentrated to yield the product as a foam (111 mg, 31%).

R_(f) 0.18 (5% Et₃N in hexane); ¹H-NMR (CDCl₃) δ 1.4-3.2 (m, 22H),3.2-3.4 (m, 1H), 3.5 (s, 3H), 3.8-3.9 (m, 1H), 6.8-7.6 (m, 33H).

EXAMPLE 45N-[(2-((3′-N′-Propyl-(1″R)-3″-(4-fluorophenyl)trop-2-ene-2″-methoxycarbonyl)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]rhenium (V) oxide(Compound 31 (Re: R=4-F), FIG. 7) (O-1135)

A solution ofN-[2-(3′-N′-propyl-(1″R)-3″-(4-fluorophenyl)trop-2-ene-2″-(methoxycarbonyl)(2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol (130 mg, 0.13mmol) in EtOH (10 mL) was heated to reflux. A solution of SnCl₂ (28 mg,0.15 mmol) in 0.005 M HCl (1.0 mL) was added quickly followedimmediately by NaReO₄ (40 mg, 0.15 mmol) in 0.005 M HCl (0.5 mL). Thesolution was refluxed for 10 h and was then applied to a chromatographycolumn (1-10% Et₃N in EtOAc). Like fractions were combined andconcentrated to yield a foam (34 mg; 37%).

R_(f) 0.09 (10% Et₃N in EtOAc); ¹H-NMR (CDCl₃) δ 1.4-4.3 (m, 23H), 3.5(s, 3H), 4.5-4.9 (m, 2H), 6.9-7.2 (m, 4H). Elemental analysis:calculated C, 41.49; H, 4.50; N, 6.05; found C, 41.77; H, 4.44; N, 5.93.Accurate mass calculated 696.1348, found 696.1405.

EXAMPLE 46N-[(2-((3′-N′-Propyl-(1″R)-3″-(3,4-dichlorophenyl)trop-2-ene-2″-methoxycarbonyl)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]rhenium (V) oxide(Compound 31 (Re: R=3,4-Cl₂), FIG. 7) (O-1136)

A solution ofN-[2-(3′-N′-propyl-(1″R)-3″-(3,4-dichlorophenyl)trop-2-ene-2″-(methoxycarbonyl)(2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol (100 mg, 0.1mmol) in EtOH (10 mL) was heated to reflux. A solution of SnCl₂ (20 mg,0.1 mmol) in 0.005 M HCl (1.0 mL) was added quickly followed immediatelyby NaReO₄ (29 mg, 0.11 mmol) in 0.005 M HCl. (0.5 mL). The solution wasrefluxed for 10 h and was then applied to a chromatography column (1-10%Et₃N in EtOAc). Like fractions were combined and concentrated to yield afoam (56 mg; 78%).

R_(f) 0.09 (10% Et₃N in EtOAc); ¹H-NMR (CDCl₃) δ 1.4-4.2 (m, 23H), 3.55(s, 3H), 4.4-4.9 (m, 2H), 6.95 (dd, 1H), 7.2 (d, 1H), 7.4 (d, 1H).Elemental analysis: calculated C, 38.65; H, 4.05; N, 5.63; found C,38.91; H, 3.96; N, 5.57. Accurate mass calculated 746.0663, found746.0689.

EXAMPLE 47N-[2-(3′-N′-Propyl-(1″R-3″β-(4-fluorophenyl)-2″β-methoxycarbonyltropane))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-2-aminoethanethiol(Compound 33 (R=4-F), FIG. 8)

To a solution of nor-3β-(4-fluorophenyl)-2β-methoxycarbonyltropane (52.6mg, 0.2 mmol) in dry acetonitrile (10 mL) was added in successionN-[2-((3-chloropropyl)-(2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenylmethyl)-2-aminoethanethiol(151 mg, 0.2 mmol), KI (33 mg, 0.2 mmol), and K₂CO₃ (280 mg, 2.0 mmol).The resulting slurry was then boiled overnight. Once the reaction wascomplete then the solution was allowed to cool to room temperature andthen 2 g of silica gel was added and the solvent evaporated. Theresulting solid was layered onto a silica gel column and eluted with0.5% NH₄OH in 1:1 solution of EtOAc and hexanes. The title compound wasrecovered as a foam in 72% yield (141 mg). This was converted to thedihydrochloride.

Mp. 166-168° C.; IR (KBr) 1666 cm⁻¹; ¹H-NMR (CDCl₃) δ 1.8-3.8, (m, 24H),3.3 (s, 3H), 3.9-4.0 (m, 1H), 4.2-4.3 (m, 1H), 4.4-4.5 (m, 1H), 6.9-7.4(m, 34 H). Elemental analysis: calculated (2 HCl.2 H₂O): C, 68.24; H,6.47; N, 3.85. Found: C, 38.03; H, 6.40; N, 3.82.

EXAMPLE 48(RS)-N-[2-((3′-N′-Propyl-(1″R-3″β-(3,4-dichlorophenyl)-2″β-methoxycarbonyltropane))(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiol (Compound 33(R=3,4-Cl₂), FIG. 8) (O-863)

Prepared identically to the compound in Example 47 above.

Mp. 108° C., IR (KBr) 1724, 1653, 957 cm⁻¹; ¹H-NMR (CDCl₃) δ 1.5-3.9 (m,22H), 3.55 & 3.50 (2s, 3H), 3.9-4.2 (m, 2H), 4.5-4.7 (m, 1H), 4.80 (d,16.4 Hz, 1H), 7.0-7.4 (m, 3H); Accurate mass calculated forC₂₄H₃₃Cl₂N₃S₂O₄Re [MH]⁺748.0819, found 748.0856. Elemental analysis:calculated, C, 38.55; H, 4.31; N, 5.62. Found C, 38.79; H, 4.38; N,5.41.

EXAMPLE 49(RS)-N-[2-((3′-N′-Propyl-(1″R-3″β-(4-fluorophenyl)-2″β-methoxycarbonyltropane))(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]rhenium (V) oxide(Compound 34 (Re: R=4-F), FIG. 8) (O-861)

N-[2-((3′-N′-Propyl-3″β-(4-fluorophenyl)tropane-2″β-carboxylic acidmethyl ester)(2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenylmethyl)-2-aminoethanethiol(98 mg, 0.1 mmol) were dissolved in boiling ethanol (1.5 mL). To thiswas added a solution of SnCl₂ (21 mg, in 200 mL of 0.05 M HCl), followedimmediately by a solution of NaReO₄ (30 mg in 200 mL of 0.05 M HCl).Boiling was continued overnight, after which boiling CH₃CN (10 mL) wasadded and the resulting solution filtered through a pad of celite. Thecake was further washed two more times with boiling CH₃CN (2×20 mL). Tothe filtrate was added silica gel (1 g) and the solvent evaporated. Thesolid was then layered onto a silica gel column and eluted with EtOAc.The title compound was isolated as a mixture of diastereomers in 90%yield (608 mg).

Mp 101.9° C., IR (KBr) 1720, 1666, 957 cm⁻¹; ¹H-NMR (CDCl₃) δ 1.4-4.2,(m, 24H), 3.46 & 3.5 (2s, 3H), 4.4-4.7 (m, 1H), 4.80 & 4.82 (2d, 16 Hz,1H), 6.8-7.3 (m, 4H); Accurate mass calculated for C₂₄H₃₄FN₃S₂O₄Re[MH]⁺698.1505, found 698.1557. This was converted to a hydrochloride foranalysis: Elemental analysis: calculated (HCl.2 H₂O) C, 37.47; H, 4.98;N, 5.46. Found C, 37.45; H, 4.95; N, 5.40.

EXAMPLE 50(RS)-N-[2-((3′-N′-Propyl-(1″R-3″β-(3,4-dichlorophenyl)-2″β-methoxycarbonyltropane))(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]rhenium (V) oxide(Compound 34 (Re: R=3,4-Cl₂), FIG. 8) (O-863)

Prepared identically to the compound in Example 49 above.

Mp. 108° C., IR (KBr) 1724, 1653, 957 cm⁻¹; ¹H-NMR (CDCl₃) δ 1.5-3.9 (m,22H), 3.55 & 3.50 (2s, 3H), 3.9-4.2 (m, 2H), 4.5-4.7 (m, 1H), 4.80 (d,16.4 Hz, 1H), 7.0-7.4 (m, 3H); Accurate mass calculated forC₂₄H₃₃Cl₂N₃S₂O₄Re [MH]⁺748.0819, found 748.0856. Elemental analysis:calculated, C, 38.55; H, 4.31; N, 5.62. Found C, 38.79; H, 4.38; N,5.41.

EXAMPLE 51(1R)-2β-Methoxycarbonyl-3α-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane(Compound 35 (R=3,4-Cl₂), FIG. 8)

(1R)-N-Methyl-2β-methoxycarbonyl-3α-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]-octane12 (375 mg, 1.14 mmol) and α-chloroethyl chloroformate (ACE-Cl) (3 mL)were combined and heated at 100° C. (oil bath temperature) for 1 h.Excess ACE-Cl was then removed under reduced pressure, and methanol (50mL) was added to the residue. The mixture was then heated at reflux for30 min and then concentrated to dryness. The residue obtained wasdissolved in CH₂Cl₂ (75 mL), washed with aqueous NH₄OH, dried overNa₂SO₄, filtered, and concentrated to afford the crude demethylatedproduct. Purification by flash chromatography (1% NH₄OH, 50-0% hexanes,50-90% EtOAc 0-10% methanol) gave 250 mg (70%) of 35.

R_(f) 0.14, (5% Et₃N/EtOAc/hexanes 1:1); ¹H-NMR (CDCl₃) δ 1.1-2.5 (m,8H), 2.9-3.3 (m, 1H), 3.5-3.8 (m, 1H), 3.6 (s, 3H), 6.95-7.40 (m, 3H).

EXAMPLE 52 (1R)-2β-Methoxycarbonyl-3α-(4-fluorophenyl)-8-azabicyclo[3.2.1]-octane(Compound 35 (R=4-F), FIG. 8)

(1R)-N-Methyl-2-methoxycarbonyl-3α-(4-fluorophenyl)-8-azabicyclo[3.2.1]-octane(95 mg, 0.34 mmol) and ACE-Cl (7 mL) were combined and heated at 100° C.(oil bath temperature) for 1 h. Excess ACE-Cl was then removed underreduced pressure, and methanol (50 mL) was added to the residue. Themixture was then heated at reflux for 30 min and then concentrated todryness. The residue obtained was dissolved in CH₂Cl₂ (75 mL), washedwith aqueous NH₄OH, dried over Na₂SO₄, filtered, and concentrated toafford the crude demethylated product. Purification by flashchromatography (0-5% NH₄OH, 10% MeOH in EtOAc) gave 86 mg (95%) of 35.

R_(f) 0.66, (10% MeOH/EtOAc+0.5% NH₄OH); ¹H-NMR (CDCl₃) δ 1.2 (ddd, 1H),1.2-2.8 (m, 5H), 3.3-3.6 (m, 2H), 3.5 (s, 3H), 3.8-4.2 (m, 2H), 6.9-7.3(m, 4H).

EXAMPLE 53N-[2-(3′-N′-Propyl-(1″R)-3″β-(3,4-dichlorophenyl)-2″β-methoxycarbonyltropane))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol(Compound 36 (R=3,4-Cl₂), FIG. 8)

To a solution of(1R)-2β-methoxycarbonyl-3α-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane 35 (250 mg, 0.79 mmol) in dry CH₃CN (40 mL) was added insuccession N-[[[2-[2-(triphenylmethyl)thio]ethyl](N′-3′-chloropropyl)amino]acetyl]-S-(triphenylmethyl)-2-aminoethanethiol(601 mg, 0.79 mmol), KI (132 mg), and K₂CO₃ (1.1 g). The resultingslurry was maintained at reflux overnight. Once the reaction wascomplete, the solution was allowed to cool to room temperature and thenpartitioned between concentrated aqueous NH₄OH and CH₂Cl₂. The layerswere separated and the organic phase dried with Na₂SO₄. The solution wasfiltered and concentrated and the residue purified by flashchromatography (15 g, SiO₂; 0-5% Et₃N in a 1:1 mixture of EtOAc/hexanes)which gave 100 mg (12%) of a white foam.

R_(f) 0.26 (2.5% NH₄OH in EtOAc/hexanes 1/1); ¹H-NMR (CDCl₃) δ 1.20-1.54(m, 5H), 1.80-2.50 (m, 15H), 2.81 (d, J=17 Hz, 1H), 2.88 (d, J=17 Hz,1H), 3.00 (m, 2H), 3.16-3.40 (m, 3H), 3.54 (s, 3H), 7.03 (dd, J=2.2, 8.5Hz, 1H), 7.14-7.53 (m, 32H). Elemental analysis: calculated, C, 72.07;H, 6.15; N, 4.07; Cl, 6.86; found C, 72.18; H, 6.21; N, 3.97; Cl, 6.75.

EXAMPLE 54N-[2-(3′-N′-Propyl-(1″R)-3″α-(4-fluorophenyl)-2″β-methoxycarbonyl-tropane))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol (Compound 36(R=4-F), FIG. 8)

To a solution of(1R)-2β-methoxycarbonyl-3α-(4-fluorophenyl)-8-azabicyclo [3.2.1]octane35 (230 mg, 0.87 mmol) in dry CH₃CN (25 mL) was added in successionN-[[[2-[2-(triphenylmethyl)thio]ethyl](N′-3′-chloropropyl)amino]acetyl]-S-(triphenylmethyl)-2-aminoethanethiol(660 mg, 0.87 mmol), KI (145 mg, 0.87 mmol), and K₂CO₃ (1.21 g, 8.7mmol). The resulting slurry was then maintained at reflux overnight.Once the reaction was complete, the solution was allowed to cool to roomtemperature and then partitioned between concentrated aqueous NH₄OH andCH₂Cl₂. The layers were separated and the organic phase dried withNa₂SO₄. The solution was filtered and concentrated and the residuepurified by flash chromatography (50% EtOAc/hexanes+1% NH₄OH) which gave435 mg (51%) of a foam.

R_(f) 0.45 (1% Et₃N, 50% EtOAc, 49% hexanes); ¹H-NMR (CDCl₃) δ 1.20 1.3(m, 1H), 1.3-2.5 (m, 19H), 2.81 (d, J=17 Hz, 1H), 2.86 (d, J=17 Hz, 1H),2.95-3.05 (m, 2H), 3.10-3.4 (m, 3H), 3.50 (s, 3H), 6.89-6.96 (m, 2H),7.1-7.5 (m, 32H). Elemental analysis: calculated (0.75 H₂O), C, 74.78;H, 6.63; N, 4.22; found C, 74.80; H, 6.64; N, 4.17.

EXAMPLE 55N-[(2-((3′-N′-Propyl-(1″R)-3″α-(4-fluorophenyl)-2″β-methoxycarbonyltropane)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]-rhenium (V) oxide(Compound 37 (R=4-F), FIG. 8) (O-1186)

A solution ofN-[2-(3′-N′-propyl-(1″R)-3″α-(4-fluorophenyl)-2″β-methoxycarbonyltropane)(2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethane-thiol (226 mg, 0.23mmol) in EtOH (10 mL) was heated to reflux. A solution of SnCl₂ (48 mg,0.25 mmol) in 0.05 M HCl (1.0 mL) was added quickly followed immediatelyby NaReO₄ (69 mg, 0.25 mmol) in 0.05 M HCl (0.5 mL). The solution wasrefluxed for 10 h and was then applied to a chromatography column (5%Et₃N in Et₂O). Like fractions were combined and concentrated to yield afoam (33 mg; 21%).

R_(f) 0.38 (10% Et₃N in EtOAc); ¹H-NMR (CDCl₃) δ 0.9-4.3 (m, 24H), 3.53,3.56 (2s, 3H), 4.4-4.7 (m, 1H), 4.75, 5.00 (2s, 1H), 6.8-7.4 (m, 4H).Elemental analysis: calculated (2/7 Et₂O) C, 42.06; H, 5.03; N, 5.85;found C, 42.08; H, 4.93; N, 5.85.

EXAMPLE 56N-[(2-((3′-N′-Propyl-(1″R)-3″α-(3,4-dichlorophenyl)-2″β-methoxycarbonyltropane)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]rhenium (V) oxide(compound 37 (R=3,4-Cl₂), FIG. 8) (O-1196)

Prepare identically to the compound in Example 55.

R_(f) 0.51 (10% Et₃N/EtOAc); ¹H-NMR (CDCl₃) δ 1.2-1.4 (m, 1H), 1.4-2.5(m, 11H), 2.89 (m, 1H), 3.10-3.40 (m, 5H), 3.56 & 3.60 (2s, 3H), 3.6-3.8(m, 0.5H), 3.90-4.15 (m, 3.5H), 4.60 (m, 1H), 4.73 & 4.95 (2d, J=16.2 &16.2 Hz, 2×0.5H), 7.0-7.1 (m, 1H), 7.24-7.36 (m, 2H). Elementalanalysis: calculated (H₂O), C, 37.64; H, 4.48; N, 5.49; found C, 37.59;H, 4.31; N, 5.55.

EXAMPLE 57(1R)-N-Methyl-2-methoxycarbonyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]oct-2-ene(Compound 50, FIG. 10)

(1R)-2-(Methoxycarbonyl)-3-[[(trifluoromethyl)sulfonyl]oxy]trop-2-ene 2(500 mg, 1.52 mmol), LiCl (142 mg, 3.34 mmol), Pd₂dba₃ (56 mg, 0.06mmol), Na₂CO₃ (2.0 M solution in water, 2 mL), diethoxymethane (6 mL)were all charged to a flask and stirred vigorously. To this solution wasadded 2-naphthyl boronic acid (340 mg, 1.97 mmol). The reaction was thenbrought to reflux for two hours and then filtered through celite. Thecake was washed with ether and all the organic solution was washed withconcentrated ammonium hydroxide solution. The washed solvent was driedwith potassium carbonate, filtered, and evaporated. The residue wascharged to a column (1-4% Et₃N/EtOAc) and gave 240 mg (51%) of compound50.

R_(f) 0.48 (10% Et₃N/EtOAc). ¹H-NMR (CDCl₃) δ 1.3-3.6 (m, 7H), 2.5 (s,3H), 3.45 (s, 3H), 3.8-4.0 (m, 1H), 7.2-8.0 (m, 7H). Elemental analysis:calculated (0.5 H₂O) C, 77.24; H, 6.94; N, 4.50; found C, 77.27; H,6.94; N, 4.48.

EXAMPLE 58(1R)-2-Methoxycarbonyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]-oct-2-ene(Compound 51, FIG. 10)

(1R)-N-Methyl-2-methoxycarbonyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]-oct-2-ene50 (100 mg, 0.33 mmol) was combined with ACE-Cl (0.25 mL) and thesolution was heated to reflux for 5 h. The excess chloroformate wasremoved in vacuo and the residue was refluxed in methanol for 45 min.The methanol was removed in vacuo and the residue was dissolved inCH₂Cl₂ and shaken with NaHCO₃/Na₂CO₃ (pH=9). The aqueous layer wasextracted CH₂Cl₂ (4×10 mL) and the combined organic extracts were dried(Na₂SO₄), filtered and concentrated. The residue was chromatographed(1-10% Et₃N/EtOAc). Like fractions were combined to yield compound 51(27 mg, 28%).

R_(f)0.15 (10% Et₃N/EtOAc); ¹H-NMR (CDCl₃) δ 1.6-2.5 (m, 5H), 2.7-3.1(m, 1H), 3.45 (s, 3H), 3.8-3.9 (m, 1H), 4.2-4.35 (m, 1H), 7.1-8.0 (m,7H).

EXAMPLE 59N-[2-(3′-N′-Propyl-(1″R)-2″-methoxycarbonyl-3″-(2-naphthyl)-trop-2-ene))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol (Compound 52,FIG. 10)

To a solution of(1R)-2-methoxycarbonyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]-oct-2-ene 51(27 mg, 0.09 mmol) in dry CH₃CN (10 mL) was added in successionN-[[[2-[2-(triphenylmethyl)thio]ethyl](N′-3′-chloropropyl)amino]acetyl]-S-(triphenylmethyl)-2-aminoethanethiol(70 mg), KI (15 mg), and K₂CO₃ (127 mg). The resulting slurry wasmaintained at reflux overnight. Once the reaction was complete, thesolution was allowed to cool to room temperature and partitioned betweenconc. aq. NH₄OH and CH₂Cl₂. The layers were separated and the organicphase dried with Na₂SO₄. The solution was filtered and concentrated andthe residue purified by flash chromatography (50-90% EtOAc/hexanes+3%NH₄OH) which gave 27 mg (29%) of 52.

R_(f) 0.44 (1% NH₄OH in EtOAc); ¹H-NMR (CDCl₃) δ 1.5-3.2 (m, 20H), 2.87(s, 2H), 3.3-3.4 (m, 1H), 3.4 (s, 3H), 3.9-4.0 (m, 1H), 7.0-7.8 (m,37H).

EXAMPLE 60N-[(2-((3′-N′-Propyl-(1″R)-2″-methoxycarbonyl-3″-(2-naphthyl)trop-2-ene)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]-rhenium (V) oxide(Compound 41, FIG. 10) (O-1185)

A solution ofN-[2-(3′-N′-propyl-(1″])-2″-methoxycarbonyl-3″-(2-naphthyl)trop-2-ene-))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol 52 (27 mg,0.027 mmol) in EtOH (10 mL) was heated to reflux. A solution of SnCl₂(5.7 mg, 0.03 mmol) in 0.05 M HCl (1.0 mL) was added quickly followedimmediately by NaReO₄ (8.2 mg, 0.03 mmol) in 0.05 M HCl (0.5 mL). Thesolution was refluxed for 10 h and was then applied to a chromatographycolumn (5% Et₃N in Et₂O). Like fractions were combined and concentratedto yield a mixture of the diastereomers (15 mg; 76%).

R_(f) 0.15 (10% Et₃N in EtOAc); IR (KBr) 967, cm⁻¹; Accurate masscalculated: 728.1599, found 728.1664; ¹H-NMR (CDCl₃) δ 1.3-4.3 (m, 23H),3.45 (s, 3H), 4.5-4.9 (m, 2H), 7.1-8.0 (m, 7H).

EXAMPLE 61(1R)-N-Methyl-2β-methoxycarbonyl-3β-(2-naphthyl)-8-azabicyclo[3.2.1]octane(Compound 42, FIG. 10) (O-1229) and(1R)-N-Methyl-2β-methoxycarbonyl-3α-(2-naphthyl)-8-azabicyclo[3.2.1]octane(Compound 43, FIG. 10) (O-1228)

To(1R)-N-Methyl-2β-methoxycarbonyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]-oct-2-ene50 (510 mg, 1.66 mmol) in THF (15 mL) at −78° C. was added SmI₂ solution(0.1 M in THF, 116 mL, 11.6 mmol) dropwise. After 30 min at −78° C. MeOH(42 mL) was added and the resulting solution stirred at −78° C. for afurther hour. The reaction was then quenched by adding TFA and water,the cold bath was also removed and the solution allowed to attain roomtemperature. The reaction was then made basic with NH₄OH and dilutedwith ether and then filtered through celite. The filter cake was washedwith more ether and then all the organic phases were combined and washedwith a sodium thiosulfate solution and then a brine solution. Afterdrying with sodium sulfate the solution was filtered and concentratedand gave the crude products which were isolated by column chromatography(0-2% Et₃N in EtOAc). Compound 42 was isolated as a light yellow solid(110 mg, 22%).

Mp. 94-95° C. R_(f) 0.28 (10% MeOH/CHCl₃); IR (KBr) 2900, 1750 cm⁻¹;¹H-NMR (CDCl₃) δ 1.5-2.3 (m, 5H), 2.25 (s, 3H), 2.7 (ddd, 1H), 2.9-3.3(m, 2H), 3.45 (s, 3H), 3.3-3.4 (m, 1H), 4.5-4.6 (m, 1H), 7.3-7.5 (m,3H), 7.7-7.9 (m, 4H). Elemental analysis: calculated (0.25 H₂O) C,76.52; H, 7.55; N, 4.46; found C, 76.63; H, 7.57; N, 4.44.

Compound 43 was isolated as an off-white solid (113 mg, 23%).

M.p. 113-114° C., R_(f) 0.56 (10% MeOH/CHCl₃); IR (KBr) 3000, 1750 cm⁻¹;¹H NMR (CDCl₃) δ 1.4-1.6 (ddd, 1H), 1.4-1.8 (m, 3H), 2.0-2.4 (m, 2H),2.3 (s, 3H), 2.4-2.7 (m, 1H), 2.65 (dd, 1H), 3.2-3.4 (m, 3H), 3.57 (s,3H), 7.2-7.5 (m, 3H). Elemental analysis: calculated C, 77.64; H, 7.49;N, 4.53; found C, 77.48; H, 7.50; N, 4.45.

EXAMPLE 62(1R)-2β-Methoxycarbonyl-3β-(²-naphthyl)-8-azabicyclo[3.2.1]-octane(Compound 44, FIG. 10)

(1R)-N-Methyl-2β-methoxycarbonyl-3β-(2-naphthyl)-8-azabicyclo[3.2.1]octane42 (146 mg) was combined with ACE-Cl (5.5 mL) and the solution washeated to reflux for 5 h. The excess chloroformate was removed in vacuoand the residue was refluxed in methanol for 45 min. The methanol wasremoved in vacuo and the residue was dissolved in CH₂Cl₂ and shaken withNaHCO₃/Na₂CO₃ (pH=9). The aqueous layer was extracted CH₂Cl₂ and thecombined organic extracts were dried (Na₂SO₄), filtered andconcentrated. The residue was chromatographed (2% MeOH/EtOAc). Likefractions were combined to yield 44 (109 mg, 78%).

R_(f) 0.27 (10% MeOH/EtOAc); ¹H-NMR (CDCl₃) δ 1.5-2.4 (m, 5H), 2.68(ddd, 1H),4.8-4.9 (m, 1H), 3.30 (s, 3H), 3.3-3.4 (m, 1H), 3.7-3.9 (m,2H), 7.1-8.0 (m, 7H). Elemental analysis: calculated (0.25 H₂O) C,76.10; H, 7.23; N, 4.67; found C, 75.98; H, 7.23; N, 4.60.

EXAMPLE 63(1R)-2β-Methoxycarbonyl-3α-(2-naphthyl)-8-azabicyclo[3.2.1]-octane(Compound 45, FIG. 10)

(1R)-N-Methyl-2β-methoxycarbonyl-3α-(2-naphthyl)-8-azabicyclo[3.2.1]-octane,43 (90 mg, 0.29 mmol) was combined with ACE-Cl (4 mL) and the solutionwas heated to reflux for 5 h. The excess chloroformate was removed invacuo and the residue was refluxed in methanol for 45 min. The methanolwas removed in vacuo and the residue was dissolved in CH₂Cl and shakenwith NaHCO₃/Na₂CO₃ (pH=9). The aqueous layer was extracted CH₂Cl and thecombined organic extracts were dried (Na₂SO₄), filtered andconcentrated. The residue was chromatographed (2% MeOH/CHCl₃). Likefractions were combined to yield 45 (109 mg, 78%).

R_(f) 0.29 (10% MeOH/CHCl₃).

EXAMPLE 64N-[2-(3′-N′-Propyl-(1″R)-2″β-methoxycarbonyl-3″β-(2-naphthyl)tropane))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol (Compound 46,FIG. 10)

To a solution of(1R)-2β-methoxycarbonyl-3β-(2-naphthyl)-8-azabicyclo[3.2.1]octane 44 (81mg, 0.27 mmol) in dry CH₃CN (20 mL) was added in successionN-[[[2-[2-(triphenylmethyl)thio]ethyl](N′-3′-chloropropyl)amino]acetyl]-S-(triphenylmethyl)-2-aminoethanethiol(207 mg), KI (46 mg, 0.27 mmol), and K₂CO₃ (378 mg). The resultingslurry was then maintained at reflux overnight. Once the reaction wascomplete, the solution was allowed to cool to room temperature and thenpartitioned between concentrated aqueous NH₄OH and CH₂Cl₂. The layerswere separated and the organic phase dried with Na₂SO₄. The solution wasfiltered and concentrated and the residue purified by flashchromatography (0-90% EtOAc/hexanes+3% NH₄OH) which gave 150 mg (54%) of46.

R_(f) 0.36 (10% Et₃N in EtOAc); ¹H-NMR (CDCl₃) δ 1.4-3.8 (m, 24H), 2.85(s, 2H), 3.38 (s, 3H), 7.0-7.8 (m, 37H).

EXAMPLE 65N-[2-(3′-N′-Propyl-(1″R)-2″β-methoxycarbonyl-3″α-(2-naphthyl)tropane))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol (Compound 47,FIG. 10)

To a solution of(1R)-2β-methoxycarbonyl-3α-(2-naphthyl)-8-azabicyclo[3.2.1]octane 45 (17mg, 0.06 mmol) in dry CH₃CN (10 mL) was added in successionN-[[[2-[2-(triphenylmethyl) thiolethyl](N′-3′-chloropropyl)amino]acetyl]-S-(triphenylmethyl)-2-aminoethanethiol(4.3 mg), KI (9.4 mg), and K₂CO₃ (79 mg). The resulting slurry was thenmaintained at reflux overnight. Once the reaction was complete, thesolution was allowed to cool to room temperature and then partitionedbetween concentrated aqueous NH₄OH and CH₂Cl₂. The layers were separatedand the organic phase dried with Na₂SO₄. The solution was filtered andconcentrated and the residue purified by flash chromatography (50-80%EtOAc/hexanes+3% NH₄OH) which gave 18 mg (31%) of 47.

R_(f) 0.16 (50% EtOAc), 47% hexane, 3% NH₄OH).

EXAMPLE 66N-[(2-((3′-N′-Propyl-(1″R)-2″β-methoxycarbonyl-3″β-(2-naphthyl)-tropane)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]-rhenium (V) oxide(Compound 48, FIG. 10) (O-1339)

A solution ofN-[2-(3′-N′-propyl-(1R)-2″β-methoxycarbonyl-3″-(2-naphthyl)-trop-2-ene))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-aminoethanethiol 46 (150 mg,0.15 mmol) in EtOH (10 mL) was heated to reflux. A solution of SnCl₂ (31mg, 0.16 mmol) in 0.05.M HCl (1.0 mL) was added quickly followedimmediately by NaReO₄ (45 mg, 0.16 mmol) in 0.05 M HCl (0.5 mL). Thesolution was refluxed for 10 h and was then applied to a chromatographycolumn (5% Et₃N in EtOAc). Like fractions were combined and concentratedto yield a mixture of the diastereomers (34 mg; 41%).

R_(f) 0.39 (10% Et₃N in EtOAc); ¹H-NMR (CDCl₃) δ 1.4-4.2 (m, 24H), 3.40,3.48 (2s, 3H), 4.4-4.7 (m, 1H), 8.25, 8.30 (2d, 1H), 7.2-8.0 (m, 7H).Elemental analysis: calculated (0.5 EtOAc) C, 46.97; H, 5.30; N, 5.39;found C, 46.91; H, 5.12; N, 5.19.

EXAMPLE 67N-[(2-((3′-N′-Propyl-(1″R)-2″β-methoxycarbonyl-3″α-(2-naphthyl)-tropane)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]-rhenium (V) oxide(Compound 49, FIG. 10)

A solution ofN-[2-(3′-N′-propyl-(1″R)-2″β-methoxycarbonyl-3″α-(2-naphthyl)-trop-2-ene))((2-((triphenylmethyl)thio)ethyl)amino)acetyl]-S-(triphenyl)-2-amino-ethanethiol 47 (18 mg,0.02 mmol) in EtOH (10 mL) was heated to reflux. A solution of SnCl₂(5.3 mg) in 0.05 M HCl (1.0 mL) was added quickly followed immediatelyby NaReO₄ (3.7 mg) in 0.05 M HCl (0.5 mL). The solution was refluxed for10 h and was then applied to a chromatography column (5% Et₃N in Et₂O).Like fractions were combined and concentrated to yield a mixture of thediastereomers (40%).

R_(f) 0.46 (5% Et₃N in EtOAc); ¹H-NMR (CDCl₃) δ 1.4-1.8 (m, 24H),1.8-2.0 (m, 2H), 2.02-2.20 (m, 1H), 2.3-2.5 (m, 3H), 2.69, 2.71 (2s,3H), 2.9-3.0 (2dd, 1H), 3.1-3.4 (m, 3H), 3.4-3.6 (m, 1H), 3.5,3.55 (2s,3H), 3.6-3.8 (2ddd, 1H), 3.9-4.2 (m, 3H), 4.5-4.7 (m, 1H), 4.75, 4.98(2d, 1H), 7.32 (d, 1H), 7.3-7.5 (m, 2H), 7.64 (s, 1H), 7.7-7.8 (m, 3H).

EXAMPLES 68-80

Tests were conducted to determine the binding affinity and selectivityof certain compounds for the dopamine transporter. The results aretabulated below.

IC50 IC50 DAT/ Example Compound DAT SERT SERT 68 O-1136 60 1693 28 69O-861 2.9 80 28 70 O-863 40 — — 71 O-927 5.0 200 40 72 O-928 3.0 30 1073 O-1185 63 960 15 74 O-1186 3.8 1300 340 75 O-1196 10 640 64 76 O-13393.6 59 16 77 O-1451 40 3260 80 78 O-1505 2.0 497 249 79 O-1508 5.9 20034 80 O-1561 5.3 337 63

EXAMPLES 81-91 ^(99m)Tc Labeling

The following compounds were prepared by identical methods describedbelow.

81N-[(2-((3′-N′-Propyl-(1″R)-2″β-methoxycarbonyl-3″α-(3,4-dichlorophenyl)-tropane)-(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]-technetium(V) oxide (Compound 37 (R=3,4-Cl₂), FIG. 8) (O-1196)

82N-[(2-((3′-N′-Propyl-(1″R)-2″β-1-propanoyl-3″α-(4-fluorophenyl)-tropane)-(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]technetium(V) oxide (Compound 19 (R=4-F), FIG. 4)

83N-[(2-((3′-N′-Propyl-(1″R)-2″β-1-propanoyl-3″α-(3,4-dichlorophenyl)-tropane)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]-technetium (V)oxide (Compound 19 (R=3,4-Cl₂), FIG. 4)

84N-[(2-((3′-N′-Propyl-(1″R)-2″β-methoxymethylcarbamoyl-3″α-(4-fluorophenyl)-tropane)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]-technetium (V)oxide (Compound 22 (R=4-F), FIG. 5) (O-1451)

85(RS)-N-[2-((3-N′-Propyl-(1″R-2″β-carbomethoxy-3″β-(4-fluorophenyl)-tropane))(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]-technetium (V)oxide (Compound 34 (R=4-F), FIG. 8)

86(RS)-N-[2-((3-N′-Propyl-(1″R-2″β-carbomethoxy-3″β-(3,4-dichlorophenyl)-tropane))(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]-technetium (V)oxide (Compound 34 (R=3,4-Cl₂), FIG. 8)

87N-[(2-((3′-N′-Propyl-(1″R)-2″-carbomethoxy-3″-(4-fluorophenyl)-tropene)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]-technetium (V)oxide (Compound 31 (R=4-F), FIG. 7)

88N-[(2-((3′-N′-Propyl-(1″R)-2″-methoxycarbonyl-3″-(3,4-dichlorophenyl)-tropene)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]-technetium (V)oxide (Compound 31 (R=3,4-Cl₂), FIG. 7)

89N-[(2-((3′-N′-Propyl-(1″R)-2″β-methoxycarbonyl-3″α-(4-fluorophenyl)-tropane)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]-technetium (V)oxide (Compound 37 (R=4-F), FIG. 8)

90N-[(2-((3′-N′-Propyl-(1″R)-3″β-(4-fluorophenyl)tropane-2″β-1-propanoyl)-(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]technetium(V) oxide (Compound 11 (R=4-F), FIG. 3)

91N-[(2-((3′-N′-Propyl-(1″R)-2″β-1-propanoyl-3″β-(3,4-dichlorophenyl)-tropane)(2-mercaptoethyl)amino)acetyl)-2-aminoethanethiolato]-technetium (V)oxide (Compound 11 (R=3,4-Cl₂), FIG. 3)

Deprotection of Tropane Analog for Radiolabeling:

The following is a description of the procedures that were employed:

Twenty microliter aliquots of TFA, CH₂Cl₂, and (C₂H₅)₃SiH were added to5.0 mg of each trityl protected precursor to cleave the thiol protectinggroup. After a 20 min. incubation, 200 L of 1.0 M HCl/Ether was added toprotonate the thiols. The solvent was evaporated off, followed bysuccessive washes with hexanes to remove the trityl groups. Thedeprotected compound was then dissolved in DMSO to produce a stocksolution at a concentration of 1 mg/mL.

Radiolabeling the Tropane Analog:

Approximately 200 mCi of sodium ^(99m)Tc pertechnetate was added to aGlucoheptonate kit (Du Pont Pharmaceuticals, Billerica, Mass.) andallowed to incubate at room temperature for 15 min. 150 mCi of theresulting ^(99m)Tc-Glucoheptonate was added to an equal volume of 50 mMAcetate Buffer, pH 5.2 (approximately 2 mL) and 50 μL of deprotectedprecursor stock solution (1 mg/mL in DMSO, 50 μg). This solution wasincubated at room temperature for 20 min. The course of theradiolabeling was monitored with a Rainin HPLC system using a reversephase Vydac C8 column (4.6×250 mm 5 μm). The column was eluted with a0.1M ammonium acetate/acetonitrile mobile phase; 1.5 mL/min. flow rate,and a gradient of 5-100% acetonitrile over 15 minutes. Radioactivedetection is achieved with a Frisk - Tech Rate meter (Bicron Corp.). Thefinal radiolabeled product was purified using a C18 Sep-Pak (WatersInc.) eluted with ethanol. For all compounds, labeling yields andradiochemical purities were greater than 85% and 98%, respectively. Eachproduct was diluted with sterile saline to yield a <10% ethanol solutionfollowed by filtration through a 0.22 μm filter prior to injection.Typical HPLC chromatograms are shown in FIGS. 11-14.

Summary of analytical results, HPLC:

With the above methodology, it was observed that the retention timeswere dependent upon two features of the analog, i.e., the conformationand the substituents. As expected the dichloro-analogs eluted later thanthe monofluorinated compounds and the boat conformers eluted later thanthe respective chair compounds. Retention times for four specific^(99m)Tc labeled compounds are tabulated below. The reproducibility was±0.1 min. Example No. Compound Retention Time(min.) Example 82 0-1505T16.6 Example 90 0-1508T 15.2 Example 83 0-1561T 17.1 Example 91 0-1506T16.1Animal Model of Parkinson's Disease:

The neurotoxin MPTP (N-methyl-1,2,3,6-tetrahydropyridine), whenadministered to monkeys, produces a spectrum of motor, cognitive,biochemical and morphological changes that is not replicated in rodents.MPTP-treated monkeys develop neurological deficits (resting tremor,rigidity, akinesia, postural abnormalities), morphological changes (cellloss in the substantia nigra, ventral tegmental area, retrorubal fields)and biochemical changes (severe depletion of DA and decreases innorepinephrine and serotonin) that closely, parallel idiopathic PD andpost-encephalitic Parkinsonism.

Two monkeys were treated with MPTP; 3-5 doses of 0.6 mg/kg administeredover 10 days. Treatment was performed under ketamine anesthesia (15mg/kg). This dose of MPTP, has previously been used to produceParkinsonism within 2-3 weeks and depletion of ³H or ¹¹C CFT bindingsites by one month. Animals treated in this manner were expected to showan inverse relationship between SPECT tracer binding and motordysfunction. The marked depletion of DA terminals produced by thistreatment should provide definitive evidence of the selectivity andsensitivity of the SPECT tracers to detect full depletion of the nerveterminals.

SPECT Imaging

All SPECT images were acquired with a MultiSPECT 2 gamma camera(Siemens, Hoffman Estates, IL) equipped with fan-beam collimators andpeaked to the 140 KeV photopeak of ^(99m)Tc (15% window). This camerahas intrinsic resolution of 4.6 mm (FWHM), and a sensitivity of ˜240cps/mCi. Images were acquired over 360° (60 projections/head, 128×128matrix) in the continuous mode. Image reconstruction was performed usinga conventional filtered back-projection algorithm to an in-planeresolution of 10 mm FWHM and attenuation correction via the Changmethod.

Rhesus monkeys weighing approximately 7 kg were anesthetized withketamine/xylazine (15.0 and 1.5 mg/kg) and positioned prone on theimaging bed of the SPECT camera. Before the start of imaging, a venouscatheter was inserted in a peripheral vein for radiopharmaceuticaladministration. The heads of the animals were immobilized with a customfabricated head holder. Approximately 20-25 mCi of ^(99m)Tc labeledO-1505T, O-1508T, O-1561T or O-1560T was injected intravenously over 60seconds. Dynamic SPECT imaging was initiated at the end of the infusionand consisted of 2 min. acquisitions during the first hour and 5 min.acquisitions thereafter.

Selectivity of for DAT Sites in the Monkey Brain

For this study, a monkey was positioned supine on the imaging table ofthe MultiSPECT 2 gamma camera and injected with ˜20 mCi of ^(99m)TcO-1560T as described above. At approximately 20 min. afterradiopharmaceutical administration, the animal was injected with CFT(1.0 mg/kg) and imaging was continued for an additional 70 min.

Image Analysis

SPECT slices with greatest striatal activity or in which the occipitalcortex was well visualized were summed and regions of interest (ROI's)were constructed. In the striatal planes, ROI's were placed on the rightand left striatum (caudate +putamen).

Radioactivity in the right and left striatum were averaged. ROIradioactivities (cpm/cc) were decay corrected to the time of injection.The difference between striatal and occipital cortex activity (specificbinding) was calculated for each image and was plotted as a function oftime. Corrections for scattered fraction and partial volume effects werenot performed.

Radiation Dosimetry

Groups of male Sprague-Dawley rats were in injected with ˜10 mCi of^(99m)Tc labeled O-1505T and O-1561T. At time intervals between 5 min.and 24 hrs after injection, groups of 6 animals injected with eachradiopharmaceutical were sacrificed and biodistribution was measured.Samples of blood, heart, lung, liver, spleen, kidney, adrenal, stomach,GI tract, testes, bone, bone marrow and skeletal muscle were weighed andradioactivity was measured with a well type gamma counter (LKB model #1282, Wallac Oy, Finland). To correct for radioactive decay and permitcalculation of the concentration of radioactivity in each organ as afraction of the administered dose, aliquots of the injected doses werecounted simultaneously. The results were expressed as percent injecteddose per gram (% I.D./g) and radiation dosimetry was estimated by theMIRdose method.

RESULTS

SPECT Imaging with 99mTc Labeled O-1505T, O-1508T, O-1561 T and O-1560T

In the images acquired early after injection of ^(99m)Tc O-1505T and^(99m)Tc O-1561T, diffuse accumulation of radioactivity was observedthroughout the brain. Over the first several minutes after injection,accumulation of tracer in the striatum intensified and the level ofradioactivity in all other structures decreased. By 30 minutes afterinjection there was excellent contrast between striatum and the rest ofthe brain. Trans-axial, sagittal and coronal images of monkey brainswere acquired between 30 and 50 minutes after injection of ^(99m)Tclabeled O-1505T, O-1508T, O-1561T and O-1560T. From these data, it isclear that the images acquired after injection of ^(99m)Tc 0-1505T and^(99m)Tc O-1561T (boat forms of the monofluoro and dichloro compounds,respectively) display high concentrations of radiopharmaceutical in thestriatum with minimal accumulation in other areas of the brain. Inparticular, lack of accumulation in the thalamus, hypothalamus ormidbrain, regions that are rich in 5-HT transporters, supports thespecificity of this tracer for DAT sites. Region of interest analysisyielded striatal to occipital cortex ratios of approximately ˜2.5 to 1.In this experiment, images acquired after injection of ^(99m)Tc O-1508Tand ^(99m)Tc O-1560T (chair forms of the monofluoro and dichlorocompounds, respectively) differed with O-1508T failing to demonstratesignificant accumulation of radioactivity in striatum or elsewhere inthe brain while O-1560T provided results more like O-1505T and O-1561T.

SPECT of MPTP Treated Monkeys

(Mid-striatal) trans-axial, sagittal and coronal SPECT images of thebrain of a rhesus monkey injected with ^(99m)Tc O-1505T were obtainedone month after MPTP treatment. Compared with normal animals, after MPTPtreatment, the level of accumulation decreased markedly and the striatumcould not be differentiated from surrounding structures.

Selectivity of 99mTc 0-1505T for DAT sites in monkey brain SPECT imagesof monkey brain showed significant accumulation of ^(99m)Tc O-1505T inthe striatum. In the early images there was diffuse accumulation ofradioactivity throughout the brain. Over the first several minutes afterinjection, accumulation of tracer in the striatum intensified and thelevel of radioactivity in all other structures decreased. By 30 minutesafter injection there was excellent contrast between striatum and therest of the brain. After injection of a receptor saturating dose ofunlabeled CFT, striatal accumulation of radioactivity decreased and by60 minutes after injection, there was no evidence of focal accumulationin the striatum.

Radiation Dosimetry

The biodistribution studies demonstrated that both ^(99m)Tc -1505T and^(99m)Tc O-1561 cleared rapidly from all tissues of the rat. For^(99m)Tc O-1505T, MIRdose calculations revealed urinary bladder to bethe target organ with a dose of 0.29 rem/mCi. Total body effective dosewas estimated at 0.037 rem/mCi

Summary:

These results demonstrate that ^(99m)Tc labeled O-1505T and O-1561T areexcellent SPECT ligands for DAT sites. These radiopharmaceuticalscombine the the following important characteristics for obtaining usefuldiagnostic images: (1) high striatal to occipital cortex ratios; (2)high selectivity for DAT vs. 5-HT transporter (SET) sites; (3)convenient preparation at high specific activity and radiochemicalpurity; (4) favorable radiation dosimetry and (5) striatal localizationrate that is well matched to the physical t½ of ^(99m)Tc.

The present invention has been described in detail, including thepreferred embodiments thereof. However, it will be appreciated thatthose skilled in the art, upon consideration of the present disclosure,may make modifications and/or improvements of this invention and stillbe within the scope and spirit of this invention as set forth in thefollowing claims:

1. A radiopharmaceutical compound which is capable of complexing with^(99m)Tc, said compound having the following structural formula:

wherein R₁ is α or β and is selected from COOR^(a), COR^(a), andCON(CH₃)OR^(a); R₂ is α or β and is selected from the group consistingof C₆H₄X, C₆H₃XY, C₁₀H₇X, and C₁₀H₆XY; R^(a) is C₁-C₅ alkyl; X and Y areindependently selected from the group consisting of R^(a), H, Br, Cl, I,F, OH, and OCH₃; L is —(CH₂)_(n) where n is an integer from 1 to 6, or—(CH₂)_(n)—(aryl, arylalkyl, ethenyl or ethynyl)-(CH₂)_(m) -where m andn are integers and the sum of n plus m is an integer from 1 to 6; and Chis a tridentate or tetradentate chelating ligand that forms a neutralcomplex with technetium or rhenium.
 2. A compound according to claim 1labeled with a radionuclide that is complexed with the chelating ligand.3. A compound according to claim 2, wherein the radionuclide is^(99m)Tc.
 4. A compound according to claim 2, wherein the radionuclideis rhenium.
 5. A compound according to claim 1, wherein the tropaneanalog has a 3α-group.
 6. A compound according to claim 1, wherein thetropane analog has a 3β-group.
 7. A compound according to claim 1,wherein the chelating ligand comprises a bisamido-bisthiol group, amonoamide, monoamino-bisthiol group or a bisamino-bisthiol groupcovalently attached to linker L.
 8. (canceled)
 9. A compound accordingto claim 1, wherein the chelating ligand isN-(2-((2-((triphenylmethyl)thio)-ethyl)amino)acetyl)-S-(triphenylmethyl)-2-aminoethanethiol.10.-17. (canceled)
 18. A method for detecting the density of tropanerecognition sites in a mammal as an indication of neurodegenerative orneuropsychiatric disorders characterized by changes in the density ofdopamine transporters or dopamine neurons, said method comprisingproviding in a suitable pharmacological carrier a radiopharmaceuticalcompound according to claim 1 labeled with ^(99m)Tc, injecting thecompound into the mammal and scanning the mammal using a radiodiagnosticimaging apparatus.
 19. A method for monitoring in a mammalneurodegenerative or neuropsychiatric disorders characterized by changesin the density of dopamine transporters or dopamine neurons, said methodcomprising providing in a suitable pharmacological carrier aradiopharmaceutical compound according to claim 1 labeled with ^(99m)Tc,injecting the compound into the mammal and scanning the mammal using aradiodiagnostic imaging apparatus.
 20. A radiopharmaceutical kit forpreparing a radiopharmaceutical preparation, said kit comprising asealed, sterile, apyrogenic vial containing a radiopharmaceuticalcompound of claim 1 and a reducing agent for labeling said compound witha radionuclide.
 21. (canceled)
 22. A compound having the followingstructural formula:

wherein R₁ is α or β and is selected from COOR^(a), COR^(a), andCON(CH₃)OR^(a); R₂ is α and is selected from C₆H₄X, C₆H₃)(Y, C₁₀H₇X, andC₁₀H₆XY; R^(a) is a C₁-C₅ alkyl; X and Y are independently selected fromR^(a), H, Br, Cl, I, F, OH, and OCH₃; wherein the compound is in the 1Ror 1S configuration; and wherein N₈ is substituted with either H or CH₃.